BOTOX® DELIVERS.

For your adult patients with incontinence due to neurogenic detrusor overactivity (NDO) refractory to an anticholinergic,

IndIcatIon detrusor overactivity associated With a neurologic condition BOTOX® for injection is indicated for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (eg, spinal cord injury [SCI], multiple sclerosis [MS]) in adults who have an inadequate response to or are intolerant of an anticholinergic medication.

IMPoRtant SaFEtY InFoRMatIon, IncLUdInG BoXEd WaRnInG

distant Spread of toxin Effect Postmarketing reports indicate that the effects of BotoX® and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. these may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. these symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening, and there have been reports of death. the risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses.

Please see additional Important Safety Information inside. Please see accompanying full Prescribing Information, including Boxed Warning.

2

More than half of patients with the following neurologic conditions may have detrusor overactivity (DO)1,2:

NDO and a Treatment

IMPoRtant SaFEtY InFoRMatIon (cont.) contRaIndIcatIonS BOTOX® is contraindicated in the presence of infection at the proposed injection site(s) and in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation.Intradetrusor injection of BOTOX® is contraindicated in patients with detrusor overactivity associated with a neurologic condition who have acute urinary tract infection, and in patients with acute urinary retention who are not routinely performing clean intermittent self-catheterization (CIC).WaRnInGS and PREcaUtIonSLack of Interchangeability Between Botulinum toxin Productsthe potency Units of BotoX® are specific to the preparation and assay method utilized. they are not interchangeable with other preparations of botulinum toxin products and, therefore, Units of biological activity of BotoX® cannot be compared to nor converted into Units of any other botulinum toxin products assessed with any other specific assay method.Spread of toxin EffectSee Boxed Warning.

Please see additional Important Safety Information on the following pages. Please see accompanying full Prescribing Information, including Boxed Warning.

BOTOX® for injection is indicated for the treatment of4:• Urinary incontinence due to detrusor overactivity associated with a neurologic condition (eg, SCI, MS)• In adults who have an inadequate response to or are intolerant of an anticholinergic medication

• Multiple sclerosis (MS)

• Spinal cord injury (SCI)

• Parkinson’s disease (PD)

• Stroke

Many patients with UI associated with a neurologic condition are inadequately managed with anticholinergics3

• 71% of patients with a neurologic condition stop taking at least one oral medication within 12 months, according to a 5-year observational study3

Patients with NDO may be using clean intermittent catheterization (CIC)1

• In BOTOX® pivotal trials for urinary incontinence (UI) due to NDO, more than half of all patients were using CIC at baseline1

• BOTOX® patients must be willing and able to perform CIC to empty the bladder4

Week 6: Primary timepoint

0 2 12 52

Treatmentregimen1

First treatment given at 0 weeks

Starting at week 12, one retreatment permitted based on patient qualification‡

Each study was at least 52 weeks in duration

Patients evaluated in the clinic at weeks 2, 6, and 12

3

Two double-blind, placebo-controlled, randomized, multicenter studies4:

Phase 3 Trials Study Design

Primary efficacy endpoint4 Select secondary efficacy endpoints4

• Weekly UI episodes• Maximum cystometric capacity (MCC)

• Maximum detrusor pressure (MDP) during first involuntary detrusor contraction (IDC)

Key patient characteristics

• Adults with UI due to detrusor overactivity associated with a neurologic condition4

– Diagnosed with MS (n=381)* or SCI (n=310)1,4†

• Spontaneously voiding or using catheterization4

– 4.5 daily UI episodes (about 32/week) on average at baseline1

• Had an inadequate response to or were intolerant of an anticholinergic medication4

* Mean baseline Expanded Disability Status Scale (EDSS) score of 5.11 (EDSS score of 5.0 = ambulatory without aid or rest for approximately 200 m; disability severe enough to impair full day activities).5

† Neurologic injury was at or below thoracic level (T1).3 68% of SCI patients were classified as ASIA A1: complete SCI with no motor or sensory function preserved in the sacral segments S4-S5.6

‡ Patient qualification for retreatment was based on loss of effect on incontinent episode frequency: 50% of effect in study 1; 70% of effect in study 2. Patients could not qualify for retreatment before week 12.1,4

Study methodology• 691 patients in 2 studies (study 1, n=416; study 2, n=275) were randomized (1:1:1)

into one of 3 arms: placebo, BOTOX® 200 U, or BOTOX® 300 U1

BOTOX® approved at 200 U for the treatment of urinary incontinence due to NDO in adults who have an inadequate response to or are intolerant of an anticholinergic medication4 • BOTOX® 300 U showed a higher rate of certain adverse events1 and no clinically meaningful difference in efficacy4

†

* †

†

0

-5

-10

-15

-20

-250 2 4 6 8 10 12 0 2 4 6 8 10 12

Mea

n ch

ange

from

bas

elin

e (e

piso

des/

wee

k)

Placebo (n=146)

BOTOX® 200 U (n=134)

Placebo (n=91)

BOTOX® 200 U (n=91)

* P<.001† P<.01 † P<.01

Weeks post-treatment Weeks post-treatment

Primary timepoint

Primary timepoint

Baseline mean weekly UI frequencyBOTOX®: 32.3 episodes; Placebo: 28.3 episodes

Baseline mean weekly UI frequencyBOTOX®: 32.7 episodes; Placebo: 36.8 episodes

Study 1 Study 2

32%

-21*-22†

36%

67%66%

-9

-13

4

BOTOX® Significantly Reduced UI Episodes

Treatment with BOTOX® 200 U reduced weekly mean UI episodes by up to 67% (-22 episodes) from baseline at week 61,4

• Placebo: up to 36% reduction (-13 episodes)

Mean change from baseline in weekly number of UI episodes1,4‡

IMPoRtant SaFEtY InFoRMatIon (cont.)WaRnInGS and PREcaUtIonS (cont.) Hypersensitivity ReactionsSerious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft-tissue edema, and dyspnea. If such a reaction occurs, further injection of BOTOX® should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined.Pre-Existing neuromuscular disordersIndividuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (eg, myasthenia gravis or Lambert-Eaton syndrome) should be monitored particularly closely when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including severe dysphagia and respiratory compromise from therapeutic doses of BOTOX®.Pulmonary Effects of BotoX® in Patients With compromised Respiratory Status treated for detrusor overactivity associated With a neurologic conditionPatients with compromised respiratory status treated with BOTOX® for detrusor overactivity associated with a neurologic condition should be monitored closely.

‡ Mean change from baseline based on LOCF analysis.

Duration of response: time to patient qualification for retreatment1,4

Study 1100

80

40

60

20

0

Per

cent

age

of p

atie

nts

not q

ualifi

ed fo

r re

trea

tmen

t

Duration of response (days) Duration of response (days)

Study 2

Starting at week 12, patients could qualify

for retreatment4

Starting at week 12, patients could qualify

for retreatment4

0 90 180 270 360 450

Placebo (n=149)

BOTOX® 200 U (n=135)

0 100 200 300 400

Placebo (n=92)

BOTOX® 200 U (n=92)

5

BOTOX® Delivered Long-lasting Response

BOTOX® patients experienced a median 10-month duration of response (up to 48 weeks) based on patient qualification for retreatment4

• Placebo: median of 4 months (up to 18 weeks)

Retreatment qualification criteria1,4

• A minimum of 12 weeks had elapsed since the first treatment• The patient requested treatment and met a UI threshold at time of request

– A return to more than 50% of baseline UI episodes in study 1– A return to more than 70% of baseline UI episodes in study 2

IMPoRtant SaFEtY InFoRMatIon (cont.)WaRnInGS and PREcaUtIonS (cont.)autonomic dysreflexia and Urinary Retention in Patients treated for detrusor overactivity associated With a neurologic conditionAutonomic dysreflexia associated with intradetrusor injections of BOTOX® could occur in patients treated for detrusor overactivity associated with a neurologic condition and may require prompt medical therapy. In clinical trials, the incidence of autonomic dysreflexia was greater in patients treated with BOTOX® 200 Units compared with placebo (1.5% versus 0.4%, respectively).In clinical trials, 30.6% of patients (33/108) who were not using clean intermittent catheterization (CIC) prior to injection, required catheterization for urinary retention following treatment with BOTOX® 200 Units as compared to 6.7% of patients (7/104) treated with placebo. The median duration of post-injection catheterization for these patients treated with BOTOX® 200 Units (n=108) was 289 days (minimum 1 day to maximum 530 days) as compared to a median duration of 358 days (minimum 2 days to maximum 379 days) for patients receiving placebo (n=104). Please see additional Important Safety Information on the following pages. Please see accompanying full Prescribing Information, including Boxed Warning.

† Change from baseline represented by LS mean change based on an LOCF analysis using an ANCOVA model.

Study 1 Study 2

+5%

+54%

+1%+12.1 mL

+135.9 mL*

+2.8 mL 259.1 mL

253.8 mL

253.8 mL 256.6 mL 271.2 mL

Baseline

Baseline Baseline

BaselineWeek 6

Week 6 Week 6

Week 6

Placebo (n=85)

BOTOX® 200 U (n=123) BOTOX® 200 U (n=88)

Placebo (n=129)

* P<.001 * P<.001

389.7 mL +63%

390.4 mL +150.8 mL*

239.6 mL

6

BOTOX® Significantly Increased Cystometric Capacity

BOTOX® patients showed a mean increase in maximum cystometric capacity of up to 63% (+150.8 mL) at week 64

• Placebo: up to 5% (+12.1 mL)

Maximum cystometric capacity at baseline and week 64†

IMPoRtant SaFEtY InFoRMatIon (cont.) WaRnInGS and PREcaUtIonS (cont.)autonomic dysreflexia and Urinary Retention in Patients treated for detrusor overactivity associated With a neurologic condition (cont.)Among patients not using CIC at baseline, those with MS were more likely to require CIC post-injection than those with SCI.Due to the risk of urinary retention, only patients who are willing and/or able to initiate catheterization post-treatment, if required, should be considered for treatment.In patients who are not catheterizing, post-void residual (PVR) urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Catheterization should be instituted if PVR urine volume exceeds 200 mL and continued until PVR falls below 200 mL. Patients should be instructed to contact their physician if they experience difficulty in voiding as catheterization may be required.Human albumin and transmission of Viral diseasesThis product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.

† Change from baseline represented by LS mean change based on an LOCF analysis using an ANCOVA model.

0

-10

-20

-30

-40

Mea

n ch

ange

from

bas

elin

e (c

mH

2O)

Study 1

-28.145%

6%

44%

-3.7

BOTOX®

200 U Placebo

Mean baseline 63.1 cmH2O

Mean baseline 57.4 cmH2O

Placebo (n=103)

BOTOX® 200 U (n=41)

Study 2

-28.7

+2.1BOTOX®

200 U

Placebo

Mean baseline 65.6 cmH2O

Mean baseline 43.7 cmH2O

Placebo (n=68)

BOTOX® 200 U (n=29)

* P<.001 * P<.001

5%10

20

* *

7

Mean change in maximum detrusor pressure during first involuntary detrusor contraction at week 61,4†

BOTOX® Significantly Reduced Detrusor Pressure

BOTOX® patients showed a mean reduction in maximum detrusor pressure at the first involuntary detrusor contraction of up to 45% (-28.1 cmH20) at week 64

• Placebo: up to 6% (-3.7 cmH20)

IMPoRtant SaFEtY InFoRMatIon (cont.) adVERSE REactIonSThe following adverse reactions to BOTOX® for injection are discussed in greater detail in the following sections: Spread of Toxin Effect (see Boxed Warning) and Hypersensitivity Reactions (see Contraindications and Warnings and Precautions).Detrusor Overactivity Associated With a Neurologic ConditionThe most frequently reported adverse reactions within 12 weeks of BOTOX® injection for detrusor overactivity associated with a neurologic condition include urinary tract infection (BOTOX® 24%, placebo 17%), urinary retention (BOTOX® 17%, placebo 3%), hematuria (BOTOX® 4%, placebo 3%), fatigue (BOTOX® 4%, placebo 1%), and insomnia (BOTOX® 2%, placebo 0%).

Please see additional Important Safety Information on the following pages. Please see accompanying full Prescribing Information, including Boxed Warning.

Adverse reactions BOTOX® 200 U (n=262)

Placebo (n=272)

Urinary tract infection (UTI) 64 (24%) 47 (17%)

Urinary retention 45 (17%) 8 (3%)

Hematuria 10 (4%) 8 (3%)

Fatigue 10 (4%) 3 (1%)

Insomnia 4 (2%) 0 (0%)

Timepoint BOTOX® 200 U Placebo

CIC prior to treatment* 119/227 (52.4%) 139/241 (57.7%)

CIC initiated at any time during complete treatment cycle† 33/108 (30.6%) 7/104 (6.7%)

* CIC status during the baseline period.† Catheterizing for urinary retention.

Proportion of patients using CIC: baseline CIC and de novo CIC following treatment1,4

• In the clinical trials, CIC was initiated at the discretion of the investigator1

• In patients who are not catheterizing, post-void residual (PVR) urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Catheterization should be instituted if PVR urine volume exceeds 200 mL and continued until PVR falls below 200 mL. Patients should be instructed to contact their physician if they experience difficulty in voiding, as catheterization may be required4

No change was observed in the overall safety profile with repeat dosing.4

* AEs reported by ≥2% of BOTOX® treated patients and more frequent than in placebo-treated patients in the first 12 weeks after intradetrusor injection in double-blind, placebo-controlled trials.4

† During the complete treatment cycle (median duration of 44 weeks of exposure) following initial injection and prior to reinjection, the BOTOX® 200 U arm experienced UTI (49%), urinary retention (17%), fatigue (6%), constipation (4%), muscular weakness (4%), dysuria (4%), fall (3%), gait disturbance (3%), insomnia (3%), and muscle spasm (2%).4

Most commonly reported adverse events (AEs) within the first 12 weeks4*†

IMPoRtant SaFEtY InFoRMatIon (cont.) adVERSE REactIonS (cont.)detrusor overactivity associated With a neurologic condition (cont.) The following adverse event rates were reported at any time following initial injection and prior to reinjection or study exit (median duration of 44 weeks of exposure): urinary tract infections (49%), urinary retention (17%), fatigue (6%), constipation (4%), muscular weakness (4%), dysuria (4%), fall (3%), gait disturbance (3%), insomnia (3%), and muscle spasm (2%).

• UTI was not required to be symptomatic; it was defined as a positive urine culture1

• Urinary retention was not defined and was determined at the discretion of the investigator1

Please see additional Important Safety Information on the following pages.

Most Commonly Reported AEs and Patient CIC Usage

8

Dome

Injection sites

Opening of left ureter

Trigone

Bladder base 1

2

1

2

9

Dosing and administration for the treatment of neurogenic detrusor overactivity

The BOTOX® Procedure Can Be Completed In-office

Pretreatment4

• Prophylactic antibiotics (except aminoglycosides) 1 to 3 days pretreatment• Patients should discontinue antiplatelet therapy at least 3 days before the injection

procedure; patients on anticoagulant therapy need to be managed appropriately to decrease the risk of bleeding

• Reconstitute 200 U of BOTOX® per label; use immediately after reconstitution in the syringe• Patients must be asymptomatic for UTI at the time of treatment; BOTOX® treatment is

contraindicated in the setting of an acute UTI

Treatment4

• Patient options for anesthesia should be discussed: no anesthesia, local anesthetic with or without sedation, or general anesthesia

• Administer prophylactic antibiotics (except aminoglycosides) on the day of treatment• Recommended dose for NDO is 200 U BOTOX® as 1-cc (~6.7 U) injections and should

not be exceeded• In treating adult patients for one or more indications, the maximum cumulative dose

should generally not exceed 360 U in a 3-month interval• Use caution when BOTOX® treatment is used in the presence of inflammation at the

proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle(s)

• Instill the bladder with enough saline to achieve adequate visualization; overdistention should be avoided

• The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX® prior to the start of the injections (depending on needle length) to remove any air

Using a flexible or rigid cystoscope, insert needle approximately 2 mm into the detrusor (avoiding the trigone)

Space injections approximately 1 cm apart

Administer 30 injections of 1 cc each (30 cc total), evenly distributed across the detrusor

– If you encounter a small amount of bleeding from an injection site, it should not interfere with the procedure1

– For the final injection, inject approximately 1 mL of sterile normal saline so the full dose is delivered

The dosing and administration of BOTOX® is a detailed process. The information on this page and the following page contain highlights only and are not meant to be a substitute for appropriate training or review of full Prescribing Information.

Please see additional Important Safety Information on the following pages. Please see accompanying full Prescribing Information, including Boxed Warning.

10

Post-treatment Protocol

30 mins

1-3 days

2 weeks

12 weeks

10 months

The potency Units of BOTOX® (onabotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products, and, therefore, units of biological activity of BOTOX® cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method.4

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

IMMEDIATELy POSTINjECTIONImmediately drain the saline used for bladder wall visualization4

30 MINUTES POSTINjECTIONObserve the patient for at least 30 minutes postinjection4

• During this period, safety monitoring and assessments should be done according to your facility’s accepted practices (eg, monitoring of blood pressure, pulse rate, and ensuring the patient has emptied the bladder before leaving the site)1

ONE TO 3 DAyS POSTINjECTIONOne to 3 days after treatment, provide postprocedural prophylactic antibiotics (except aminoglycosides)4

2 TO 12 WEEkS POSTINjECTIONAssess PVR volume within 2 weeks post-treatment (or earlier as medically appropriate) for patients who are not catheterizing4

Continue to assess PVR volume periodically as medically appropriate up to 12 weeks post-treatment4

RETREATMENT CONSIDERATIONS Reinjection may be considered upon diminishing clinical effect of the previous BOTOX® injection (median time to qualification for retreatment in the double-blind, placebo-controlled clinical studies was approximately 10 months [42 to 48 weeks] for BOTOX® 200 U) but no sooner than 12 weeks from the prior bladder injection procedure4

11

BOTOX® treatment for NDO is generally well covered by private and public payers7

Coverage and Reimbursement

IMPoRtant SaFEtY InFoRMatIon (cont.) dRUG IntERactIonSNo formal drug interaction studies have been conducted with BOTOX® (onabotulinumtoxinA) for injection. Co-administration of BOTOX® and aminoglycosides or other agents interfering with neuromuscular transmission (e.g. curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated. Use of anticholinergic drugs after administration of BOTOX® may potentiate systemic anticholinergic effects.

Established J-code for BOTOX® for over 20 years1

• J-code = J0585

• Acquisition cost for 200 U = $1050

Selecting a procedural code is a clinical decision

• Currently no specific CPT® code exists for BOTOX® bladder injections

• AUA states that in absence of an established code, CPT code 53899 (unlisted procedure, urinary system) may be used

Simplify reimbursement with Allergan resourcesBOTOX® Reimbursement Solutions

• 20 years of experience in BOTOX® reimbursement for therapeutic uses

• Provides urology offices with comprehensive support for insurance verification, prior authorization, and claims appeals

• Verification of coverage and benefits for each of your patients

• Click on BOTOXReimbursementSolutions.com for a wide range of online tools

• Call the BOTOX® Reimbursement Solutions Support Center at 1-800-44-BOTOX (1-800-442-6869), Option 4, for direct access to Reimbursement Counselors

Reimbursement Business Managers • On-site education, training, and support

• Knowledge of your local payers’ policies

• Use the Reimbursement Business Manager Lookup feature at BOTOXReimbursementSolutions.com

Please see additional Important Safety Information on the following pages. Please see accompanying full Prescribing Information, including Boxed Warning.

BOTOX®

DELIVERS.

* Patient qualification for retreatment was based on loss of effect on incontinent episode frequency: 50% of effect in study 1; 70% of effect in study 2. Patients could not qualify for retreatment before week 12.1,4

Please see accompanying full Prescribing Information, including Boxed Warning.

References:1. Data on file, Allergan, Inc. 2. Fynewever TL, Siddigh S. Management of detrusor overactivity. In: Siddighi S, Hardesty JS, eds. Urogynecology and Female Pelvic Reconstructive Surgery: Just the Facts. New York, NY: McGraw-Hill; 2006:169-176. 3. Manack A, et al. Neurourol Urodyn. 2011;30(3): 395-401. 4. BOTOX® Prescribing Information, November 2011. 5. Kurtzke Expanded Disability Status Scale. 6. American Spinal Injury Association (ASIA). Available at: www.asia-spinalinjury.org/publications/59544_sc_Exam_Sheet_r4.pdf. Accessed January 4, 2012. 7. Managed Markets Insight & Technology, LLC, as of December 2011.

Significantly Reduced UI EpisodesTreatment with BOTOX® 200 U reduced weekly mean UI episodes by up to 67% (-22 episodes) from baseline vs up to 36% (-13 episodes) for placebo by week 6.1,4

Long-lasting ResponseBOTOX® patients experienced a median 10-month duration of response (up to 48 weeks) vs 4 months (up to 18 weeks) for placebo based on patient qualification for retreatment.4*

Significantly Improved Urodynamic ParametersBOTOX® patients showed a mean increase from baseline in maximum cystometric capacity of up to 63% (+150.8 mL) vs up to 5% (+12.1 mL) for placebo.4

IMPoRtant SaFEtY InFoRMatIon (cont.) dRUG IntERactIonS (cont.)The effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of BOTOX®.

CPT is a registered trademark of the American Medical Association.©2012 Allergan, Inc., Irvine, CA 92612 ® marks owned by Allergan, Inc. www.BOTOXMedical.com/HCP 1-800-44-BOTOX APC74IY12 ALBNUI50285

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BOTOX® safely and effectively. See full prescribing information for BOTOX. BOTOX (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor, or intradermal use Initial U.S. Approval: 1989

WARNING: DISTANT SPREAD OF TOXIN EFFECT See full prescribing information for complete boxed warning. The effects of BOTOX and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms. (5.2)

RECENT MAJOR CHANGES• IndicationsandUsage,DetrusorOveractivityassociatedwithaNeurologicCondition(1.1)8/2011

• DosageandAdministration,DetrusorOveractivityassociatedwithaNeurologicCondition(2.3)8/2011

• Contraindications,AcuteUrinaryTractInfectionandAcuteUrinaryRetention(4.3)8/2011

• WarningsandPrecautions,InjectionsInorNearVulnerableAnatomicStructures(5.3)11/2011

• WarningsandPrecautions,AutonomicDysreflexiaandUrinaryRetentioninPatientsTreatedforDetrusorOveractivityassociatedwithaNeurologicCondition(5.11)8/2011

INDICATIONS AND USAGEBOTOXisanacetylcholinereleaseinhibitorandaneuromuscularblockingagentindicatedfor:• Treatmentofurinaryincontinenceduetodetrusoroveractivityassociatedwithaneurologiccondition[e.g.,spinalcordinjury(SCI),multiplesclerosis(MS)]inadultswhohaveaninadequateresponsetoorareintolerantofananticholinergicmedication(1.1)

• Prophylaxisofheadachesinadultpatientswithchronicmigraine(≥15dayspermonthwithheadachelasting4hoursadayorlonger)(1.2)

• Treatmentofupperlimbspasticityinadultpatients(1.3)• Treatmentofcervicaldystoniainadultpatients,toreducetheseverityofabnormalheadpositionandneckpain(1.4)

• Treatmentofsevereaxillaryhyperhidrosisthatisinadequatelymanagedbytopicalagentsinadultpatients(1.5)

• Treatmentofblepharospasmassociatedwithdystoniainpatients≥12yearsofage(1.6)

• Treatmentofstrabismusinpatients≥12yearsofage(1.6)Important limitations:• SafetyandeffectivenessofBOTOXhavenotbeenestablishedfortheprophylaxisofepisodicmigraine(14headachedaysorfewerpermonth).(1.2)

• SafetyandeffectivenessofBOTOXhavenotbeenestablishedforthetreatmentofupperlimbspasticityinpediatricpatients,andforthetreatmentoflowerlimbspasticityinadultandpediatricpatients.(1.3)

• SafetyandeffectivenessofBOTOXforhyperhidrosisinbodyareasotherthanaxillaryhavenotbeenestablished.(1.5)

DOSAGE AND ADMINISTRATION• Indicationspecificdosageandadministrationrecommendationsshouldbefollowed;Donotexceedatotaldoseof360Unitsadministeredina3monthinterval(2.1)

• SeePreparationandDilutionTechniqueforinstructionsonBOTOXreconstitution,storage,andpreparationbeforeinjection(2.2)

• DetrusorOveractivityassociatedwithaNeurologicCondition:Recommendedtotaldose200Units,as1mL(~6.7Units)injectionsacross30sitesintothedetrusor(2.3)

• ChronicMigraine:Recommendedtotaldose155Units,as0.1mL(5Units)injectionspereachsitedividedacross7head/neckmuscles(2.4)

• UpperLimbSpasticity:Selectdosebasedonmusclesaffected,severityofmuscleactivity,priorresponsetotreatment,andadverseeventhistory;Electromyographicguidancerecommended(2.5)

• CervicalDystonia:Basedosingonthepatient’sheadandneckposition,localizationofpain,musclehypertrophy,patientresponse,andadverseeventhistory;uselowerinitialdoseinbotulinumtoxinnaïvepatients(2.6)

•AxillaryHyperhidrosis:50Unitsperaxilla(2.7)• Blepharospasm:1.25Units-2.5Unitsintoeachof3sitesperaffectedeye(2.8)

•Strabismus:1.25Units-2.5Unitsinitiallyinanyonemuscle(2.9)DOSAGE FORMS AND STRENGTHS

Single-use,sterile100Unitsor200Unitsvacuum-driedpowderforreconstitutiononlywithsterile,non-preserved0.9%SodiumChlorideInjectionUSPpriortoinjection(3)

CONTRAINDICATIONS• Hypersensitivitytoanybotulinumtoxinpreparationortoanyofthecomponentsintheformulation(4.1,5.4,6)

• Infectionattheproposedinjectionsite(4.2)• IntradetrusorInjections:AcuteUrinaryTractInfectionand/orAcuteUrinaryRetention(4.3)

WARNINGS AND PRECAUTIONS• PotencyUnitsofBOTOXnotinterchangeablewithotherpreparationsofbotulinumtoxinproducts(5.1,11)

• Spreadoftoxineffects;swallowingandbreathingdifficultiescanleadtodeath.Seekimmediatemedicalattentionifrespiratory,speechorswallowingdifficultiesoccur(5.2,5.5)

• Careshouldbetakenwheninjectinginornearvulnerableanatomicstructures(5.3)

• Concomitantneuromusculardisordermayexacerbateclinicaleffectsoftreatment(5.6)

• Usewithcautioninpatientswithcompromisedrespiratoryfunction(5.5,5.7,5.10)

• CornealexposureandulcerationduetoreducedblinkingmayoccurwithBOTOXtreatmentofblepharospasm(5.8)

• RetrobulbarhemorrhagesandcompromisedretinalcirculationmayoccurwithBOTOXtreatmentofstrabismus(5.9)

• Bronchitisandupperrespiratorytractinfectionsinpatientstreatedforupperlimbspasticity(5.10)

• Urinaryretention:Post-voidresidualurinevolumeshouldbemonitoredinpatientstreatedfordetrusoroveractivityassociatedwithaneurologicconditionwhodonotcatheterizeroutinely,particularlypatientswithMS.(5.11)

ADVERSE REACTIONSThemostcommonadversereactions(≥5%and>placebo)are(6.1):• DetrusorOveractivityassociatedwithaneurologiccondition:urinarytractinfection,urinaryretention

•ChronicMigraine:neckpain,headache•Spasticity:paininextremity• CervicalDystonia:dysphagia,upperrespiratoryinfection,neckpain,headache,increasedcough,flusyndrome,backpain,rhinitis

• AxillaryHyperhidrosis:injectionsitepainandhemorrhage,non-axillarysweating,pharyngitis,flusyndrome

To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS• PatientsreceivingconcomitanttreatmentofBOTOXandaminoglycosidesorotheragentsinterferingwithneuromusculartransmission(e.g.,curare-likeagents),ormusclerelaxants,shouldbeobservedcloselybecausetheeffectofBOTOXmaybepotentiated(7)

USE IN SPECIFIC POPULATIONS•Pregnancy:Basedonanimaldata,maycausefetalharm(8.1)• PediatricUse:Safetyandefficacyarenotestablishedinpatientsunder18yearsofagefortheprophylaxisofheadachesinchronicmigraine,thetreatmentofdetrusoroveractivityassociatedwithaneurologiccondition,upperlimbspasticity,andaxillaryhyperhidrosis,inpatientsunder16yearsofageforthetreatmentofcervicaldystonia,andinpatientsunder12yearsofageforthetreatmentofblepharospasmandstrabismus(8.4)

See 17 for PATIENT COUNSELING INFORMATION and Medication GuideRevised: 11/2011

FULL PRESCRIBING INFORMATION: CONTENTS*WARNING: DISTANT SPREAD OF TOXIN EFFECT1 INDICATIONS AND USAGE 1.1 DetrusorOveractivityassociatedwithaNeurologicCondition 1.2 ChronicMigraine 1.3 UpperLimbSpasticity 1.4 CervicalDystonia 1.5 PrimaryAxillaryHyperhidrosis 1.6 BlepharospasmandStrabismus2 DOSAGE AND ADMINISTRATION 2.1 InstructionsforSafeUse 2.2 PreparationandDilutionTechnique

2.3 DetrusorOveractivityassociatedwithaNeurologicCondition 2.4 ChronicMigraine 2.5 UpperLimbSpasticity 2.6 CervicalDystonia 2.7 PrimaryAxillaryHyperhidrosis 2.8 Blepharospasm 2.9 Strabismus3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 KnownHypersensitivitytoBotulinumToxin 4.2 InfectionattheInjectionSite(s) 4.3 AcuteUrinaryTractInfectionand/orAcuteUrinaryRetention

FULL PRESCRIBING INFORMATION

WARNING: DISTANT SPREAD OF TOXIN EFFECT Postmarketing reports indicate that the effects of BOTOX and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses. [See Warnings and Precautions (5.2)]

1 INDICATIONS AND USAGE1.1 Detrusor Overactivity associated with a Neurologic ConditionBOTOX(onabotulinumtoxinA)forinjectionisindicatedforthetreatmentofurinaryincontinenceduetodetrusoroveractivityassociatedwithaneurologiccondition(e.g.,SCI,MS)inadultswhohaveaninadequateresponsetoorareintolerantofananticholinergicmedication.

1.2 Chronic MigraineBOTOXisindicatedfortheprophylaxisofheadachesinadultpatientswithchronicmigraine(≥15dayspermonthwithheadachelasting4hoursadayorlonger).

Important limitationsSafetyandeffectivenesshavenotbeenestablishedfortheprophylaxisofepisodicmigraine(14headachedaysorfewerpermonth)insevenplacebo-controlledstudies.

1.3 Upper Limb SpasticityBOTOX isindicatedforthetreatmentofupperlimbspasticityinadultpatients,todecreasetheseverityofincreasedmuscletoneinelbowflexors(biceps),wristflexors(flexorcarpiradialisandflexorcarpiulnaris)andfingerflexors(flexordigitorumprofundusandflexordigitorumsublimis).

Important limitationsSafetyandeffectivenessofBOTOXhavenotbeenestablishedforthetreatmentofotherupperlimbmusclegroups,orforthetreatmentoflowerlimbspasticity.SafetyandeffectivenessofBOTOXhavenotbeenestablishedforthetreatmentofspasticityinpediatricpatientsunderage18years.BOTOXhasnotbeenshowntoimproveupperextremityfunctionalabilities,orrangeofmotionatajointaffectedbyafixedcontracture.TreatmentwithBOTOXisnotintendedtosubstituteforusualstandardofcarerehabilitationregimens.

1.4 Cervical Dystonia BOTOXisindicatedforthetreatmentofadultswithcervicaldystonia,toreducetheseverityofabnormalheadpositionandneckpainassociatedwithcervicaldystonia.

1.5 Primary Axillary HyperhidrosisBOTOXisindicatedforthetreatmentofsevereprimaryaxillaryhyperhidrosisthatisinadequatelymanagedwithtopicalagents.

Important limitationsThesafetyandeffectivenessofBOTOXforhyperhidrosisinotherbodyareashavenotbeenestablished.WeaknessofhandmusclesandblepharoptosismayoccurinpatientswhoreceiveBOTOXforpalmarhyperhidrosisandfacialhyperhidrosis,respectively.Patientsshouldbeevaluatedforpotentialcausesofsecondaryhyperhidrosis(e.g.,hyperthyroidism)toavoidsymptomatictreatmentofhyperhidrosiswithoutthediagnosisand/ortreatmentoftheunderlyingdisease.

SafetyandeffectivenessofBOTOXhavenotbeenestablishedforthetreatmentofaxillaryhyperhidrosisinpediatricpatientsunderage18.

1.6 Blepharospasm and StrabismusBOTOXisindicatedforthetreatmentofstrabismusandblepharospasmassociatedwithdystonia,includingbenignessentialblepharospasmorVIInervedisordersinpatients12yearsofageandabove.

2 DOSAGE AND ADMINISTRATION2.1 Instructions for Safe UseThe potency Units of BOTOX (onabotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method[see Warnings and Precautions (5.1) and Description (11)].Indicationspecificdosageandadministrationrecommendationsshouldbefollowed.Intreatingadultpatientsforoneormoreindications,themaximumcumulativedoseshouldgenerallynotexceed360Units,ina3monthinterval.

ThesafeandeffectiveuseofBOTOXdependsuponproperstorageoftheproduct,selectionofthecorrectdose,andproperreconstitutionandadministrationtechniques.PhysiciansadministeringBOTOXmustunderstandtherelevantneuromuscularand/ororbitalanatomyoftheareainvolvedandanyalterationstotheanatomyduetopriorsurgicalprocedures.Anunderstandingofstandardelectromyographictechniquesisalsorequiredfortreatmentofstrabismusandofupperlimbspasticity,andmaybeusefulforthetreatmentofcervicaldystonia.

UsecautionwhenBOTOXtreatmentisusedinthepresenceofinflammationattheproposedinjectionsite(s)orwhenexcessiveweaknessoratrophyispresentinthetargetmuscle(s).

2.2 Preparation and Dilution TechniqueBOTOXissuppliedinsingle-use100Unitsand200Unitspervial.Priortoinjection,reconstituteeachvacuum-driedvialofBOTOXwithsterile,non-preserved0.9%SodiumChlorideInjectionUSP.Drawuptheproperamountofdiluentintheappropriatesizesyringe(seeTable1,orforspecificinstructionsfordetrusoroveractivityassociatedwithaneurologicconditionseeSection2.3),andslowlyinjectthediluentintothevial.Discardthevialifavacuumdoesnotpullthediluentintothevial.GentlymixBOTOXwiththesalinebyrotatingthevial.Recordthedateandtimeofreconstitutiononthespaceonthelabel.BOTOXshouldbeadministeredwithin24hoursafterreconstitution.Duringthistimeperiod,reconstitutedBOTOXshouldbestoredinarefrigerator(2°to8°C).

5 WARNINGS AND PRECAUTIONS 5.1 LackofInterchangeabilitybetweenBotulinumToxinProducts 5.2 SpreadofToxinEffect 5.3 InjectionsInorNearVulnerableAnatomicStructures 5.4 HypersensitivityReactions 5.5 DysphagiaandBreathingDifficultiesinTreatmentofCervicalDystonia 5.6 Pre-ExistingNeuromuscularDisorders 5.7 PulmonaryEffectsofBOTOXinPatientswithCompromised

RespiratoryStatusTreatedforSpasticityorforDetrusorOveractivityassociatedwithaNeurologicCondition

5.8 CornealExposureandUlcerationinPatientsTreatedwithBOTOXforBlepharospasm

5.9 RetrobulbarHemorrhagesinPatientsTreatedwithBOTOXforStrabismus

5.10 BronchitisandUpperRespiratoryTractInfectionsinPatientsTreatedforSpasticity

5.11 AutonomicDysreflexiaandUrinaryRetentioninPatientsTreatedforDetrusorOveractivityassociatedwithaNeurologicCondition

5.12 HumanAlbuminandTransmissionofViralDiseases6 ADVERSE REACTIONS 6.1 ClinicalTrialsExperience 6.2 Immunogenicity 6.3 Post-MarketingExperience7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 NursingMothers

8.4 PediatricUse 8.5 GeriatricUse10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 MechanismofAction 12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility 13.2 AnimalToxicology14 CLINICAL STUDIES 14.1 DetrusorOveractivityassociatedwithaNeurologicCondition 14.2 ChronicMigraine 14.3 UpperLimbSpasticity 14.4 CervicalDystonia 14.5 PrimaryAxillaryHyperhidrosis 14.6 Blepharospasm 14.7 Strabismus16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION 17.1 Swallowing,SpeakingorBreathingDifficulties,orOther

UnusualSymptoms 17.2 AbilitytoOperateMachineryorVehicles 17.3 VoidingDifficultiesafterBladderInjections

*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted

Table 1: Dilution Instructions for BOTOX Vials (100 Units and 200 Units)

Diluent* Added to

100 Unit Vial

Resulting Dose Units per 0.1 mL

Diluent* Added to

200 Unit Vial

Resulting Dose Units per 0.1 mL

1mL 10Units 1mL 20Units

2mL 5Units 2mL 10Units

4mL 2.5Units 4mL 5Units

8mL 1.25Units 8mL 2.5Units

10mL 2Units

*Preservative-free0.9%SodiumChlorideInjection,USPOnly

Note:Thesedilutionsarecalculatedforaninjectionvolumeof0.1mL.AdecreaseorincreaseintheBOTOXdoseisalsopossiblebyadministeringasmallerorlargerinjectionvolume-from0.05mL(50%decreaseindose)to0.15mL(50%increaseindose).

AninjectionofBOTOXispreparedbydrawingintoanappropriatelysizedsterilesyringeanamountoftheproperlyreconstitutedtoxinslightlygreaterthantheintendeddose.Airbubblesinthesyringebarrelareexpelledandthesyringeisattachedtoanappropriateinjectionneedle.Patencyoftheneedleshouldbeconfirmed.Anew,sterile,needleandsyringeshouldbeusedtoenterthevialoneachoccasionforremovalofBOTOX.ReconstitutedBOTOXshouldbeclear,colorless,andfreeofparticulatematter.Parenteraldrugproductsshouldbeinspectedvisuallyforparticulatematteranddiscolorationpriortoadministrationandwheneverthesolutionandthecontainerpermit.

2.3 Detrusor Overactivity associated with a Neurologic ConditionPatientsshouldnothaveanacuteurinarytractinfectionpriortotreatment.Prophylacticantibiotics(exceptaminoglycosides,see Drug Interactions (7))shouldbeadministered1-3dayspre-treatment,onthetreatmentday,and1-3dayspost-treatment.

Patientsshoulddiscontinueanti-platelettherapyatleast3daysbeforetheinjectionprocedure.Patientsonanti-coagulanttherapyneedtobemanagedappropriatelytodecreasetheriskofbleeding.

Appropriatecautionshouldbeexercisedwhenperformingacystoscopy.

Anintravesicalinstillationofdilutedlocalanestheticwithorwithoutsedation,orgeneralanesthesiamaybeusedpriortoinjection,perlocalsitepractice.Ifalocalanestheticinstillationisperformed,thebladdershouldbedrainedandirrigatedwithsterilesalinebeforeinjection.

Therecommendeddoseis200UnitsofBOTOXpertreatment,andshouldnotbeexceeded.

Reconstitutea200UnitvialofBOTOXwith6mLof0.9%non-preservedsalinesolutionandmixthevialgently.Draw2mLfromthevialintoeachofthree10mLsyringes.Completethereconstitutionbyadding8mLof0.9%non-preservedsalinesolutionintoeachofthe10mLsyringes,andmixgently.Thiswillresultinthree10mLsyringeseachcontaining10mL(~67Unitsineach),foratotalof200UnitsofreconstitutedBOTOX.Useimmediatelyafterreconstitutioninthesyringe.Disposeofanyunusedsaline.

Alternatively,reconstitutetwo100UnitvialsofBOTOX,eachwith6mLof0.9%non-preservedsalinesolutionandmixthevialsgently.Draw4mLfromeachvialintoeachoftwo10mLsyringes.Drawtheremaining2mLfromeachvialintoathird10mLsyringe.Completethereconstitutionbyadding6mLof0.9%non-preservedsalinesolutionintoeachofthe10mLsyringes,andmixgently.Thiswillresultinthree10mLsyringeseachcontaining10mL(~67Unitsineach),foratotalof200UnitsofreconstitutedBOTOX.Useimmediatelyafterreconstitutioninthesyringe.Disposeofanyunusedsaline.

ReconstitutedBOTOX(200Units/30mL)isinjectedintothedetrusormuscleviaaflexibleorrigidcystoscope,avoidingthetrigone.Thebladdershouldbeinstilledwithenoughsalinetoachieveadequatevisualizationfortheinjections,butover-distensionshouldbeavoided.

Theinjectionneedleshouldbefilled(primed)withapproximately1mLofreconstitutedBOTOXpriortothestartofinjections(dependingontheneedlelength)toremoveanyair.

Theneedleshouldbeinsertedapproximately2mmintothedetrusor,and30injectionsof1mL(~6.7Units)each(totalvolumeof30mL)shouldbespacedapproximately1cmapart(seeFigure1).Forthefinalinjection,approximately1mLofsterilenormalsalineshouldbeinjectedsothefulldoseisdelivered.Aftertheinjectionsaregiven,thesalineusedforbladderwallvisualizationshouldbedrained.Thepatientshouldbeobservedforatleast30minutespost-injection.

Patientsshouldbeconsideredforre-injectionwhentheclinicaleffectofthepreviousinjectiondiminishes(mediantimetoqualificationforre-treatmentinthedouble-blind,placebo-controlledclinicalstudieswas295-337days[42-48weeks]forBOTOX200Units),butnosoonerthan12weeksfromthepriorbladderinjection.

Figure 1: Injection Pattern for Detrusor Overactivity associated with a Neurologic Condition

2.4 Chronic MigraineTherecommendeddilutionis200Units/4mLor100Units/2mL,withafinalconcentrationof5Unitsper0.1mL(seeTable1).Therecommendeddosefortreatingchronicmigraineis155Unitsadministeredintramuscularly(IM)usingasterile30-gauge,0.5inchneedleas0.1mL(5Units)injectionspereachsite.Injectionsshouldbedividedacross7specifichead/neckmuscleareasasspecifiedinthediagramsandTable2below.Aoneinchneedlemaybeneededintheneckregionforpatientswiththickneckmuscles.Withtheexceptionoftheprocerusmuscle,whichshouldbeinjectedatonesite(midline),allmusclesshouldbeinjectedbilaterallywithhalfthenumberofinjectionsitesadministeredtotheleft,andhalftotherightsideoftheheadandneck.Therecommendedre-treatmentscheduleisevery12weeks.

Diagrams1-4:RecommendedInjectionSites(AthruG)forChronicMigraine

1 2 3 4

A. Corrugator: 5 U each side

D. Temporalis: 20 U each side

E. Occipitalis: 15 U each side

F. Cervical paraspinal: 10 U each side

B. Procerus: 5 U (one site)

G. Trapezius: 15 U each side

C. Frontalis: 10 U each side

Table 2: BOTOX Dosing by Muscle for Chronic Migraine

Head/Neck Area Recommended Dose (Number of Sitesa)

Frontalisb 20Unitsdividedin4sites

Corrugatorb 10Unitsdividedin2sites

Procerus 5Unitsin1site

Occipitalisb 30Unitsdividedin6sites

Temporalisb 40Unitsdividedin8sites

Trapeziusb 30Unitsdividedin6sites

CervicalParaspinalMuscleGroupb 20Unitsdividedin4sites

Total Dose: 155 Units divided in 31 sitesa Each IM injection site = 0.1 mL = 5 Units BOTOX b Dose distributed bilaterally

2.5 Upper Limb SpasticityDosingininitialandsequentialtreatmentsessionsshouldbetailoredtotheindividualbasedonthesize,numberandlocationofmusclesinvolved,severityofspasticity,thepresenceoflocalmuscleweakness,thepatient’sresponsetoprevioustreatment,oradverseeventhistorywithBOTOX.Inclinicaltrials,dosesrangingfrom75Unitsto360Unitsweredividedamongselectedmusclesatagiventreatmentsession.

Table 3: BOTOX Dosing by Muscle for Upper Limb Spasticity

Muscle Recommended Dose Total Dosage (Number of Sites)

BicepsBrachii 100Units-200Unitsdividedin4sites

FlexorCarpiRadialis 12.5Units-50Unitsin1site

FlexorCarpiUlnaris 12.5Units-50Unitsin1site

FlexorDigitorumProfundus 30Units-50Unitsin1site

FlexorDigitorumSublimis 30Units-50Unitsin1site

Therecommendeddilutionis200Units/4mLor100Units/2mLwith0.9%non-preservedsterilesaline(seeTable1).Thelowestrecommendedstartingdoseshouldbeused,andnomorethan50Unitspersiteshouldgenerallybeadministered.Anappropriatelysizedneedle(e.g.,25-30gauge)maybeusedforsuperficialmuscles,andalonger22gaugeneedlemaybeusedfordeepermusculature.Localizationoftheinvolvedmuscleswithelectromyographicguidanceornervestimulationtechniquesisrecommended.

RepeatBOTOXtreatmentmaybeadministeredwhentheeffectofapreviousinjectionhasdiminished,butgenerallynosoonerthan12weeksafterthepreviousinjection.Thedegreeandpatternofmusclespasticityatthetimeofre-injectionmaynecessitatealterationsinthedoseofBOTOXandmusclestobeinjected.

2.6 Cervical DystoniaAdouble-blind,placebo-controlledstudyenrolledpatientswhohadextendedhistoriesofreceivingandtoleratingBOTOXinjections,withpriorindividualizedadjustmentofdose.ThemeanBOTOXdoseadministeredtopatientsinthisstudywas236Units(25thto75thpercentilerangeof198Unitsto300Units).TheBOTOXdosewasdividedamongtheaffectedmuscles[see Clinical Studies (14.4)].

Dosingininitialandsequentialtreatmentsessionsshouldbetailoredtotheindividualpatientbasedonthepatient’sheadandneckposition,localizationofpain,musclehypertrophy,patientresponse,andadverseeventhistory.TheinitialdoseforapatientwithoutprioruseofBOTOXshouldbeatalowerdose,withsubsequentdosingadjustedbasedonindividualresponse.Limitingthetotaldoseinjectedintothesternocleidomastoidmuscleto100Unitsorlessmaydecreasetheoccurrenceofdysphagia[see Warnings and Precautions (5.2, 5.5, 5.6)].

Therecommendeddilutionis200Units/2mL,200Units/4mL,100Units/1mL,or100Units/2mLwith0.9%non-preservedsterilesaline,dependingonvolumeandnumberofinjectionsitesdesiredtoachievetreatmentobjectives(seeTable1).Ingeneral,nomorethan50Unitspersiteshouldbeadministered.Anappropriatelysizedneedle(e.g.,25-30gauge)maybeusedforsuperficialmuscles,andalonger22gaugeneedlemaybeusedfordeepermusculature.Localizationoftheinvolvedmuscleswithelectromyographicguidancemaybeuseful.

Clinicalimprovementgenerallybeginswithinthefirsttwoweeksafterinjectionwithmaximumclinicalbenefitatapproximatelysixweekspost-injection.Inthedouble-blind,placebo-controlledstudymostsubjectswereobservedtohavereturnedtopre-treatmentstatusby3monthspost-treatment.

2.7 Primary Axillary HyperhidrosisTherecommendeddoseis50Unitsperaxilla.Thehyperhidroticareatobeinjectedshouldbedefinedusingstandardstainingtechniques,e.g.,Minor’sIodine-StarchTest.Therecommendeddilutionis100Units/4mLwith0.9%preservative-freesterilesaline(seeDilutionTable).Usinga30gaugeneedle,50UnitsofBOTOX(2mL)isinjectedintradermallyin0.1to0.2mLaliquotstoeachaxillaevenlydistributedinmultiplesites(10-15)approximately1-2cmapart.

Repeatinjectionsforhyperhidrosisshouldbeadministeredwhentheclinicaleffectofapreviousinjectiondiminishes.

Instructions for the Minor’s Iodine-Starch Test Procedure:Patientsshouldshaveunderarmsandabstainfromuseofover-the-counterdeodorantsorantiperspirantsfor24hourspriortothetest.Patientshouldberestingcomfortablywithoutexercise,hotdrinksforapproximately30minutespriortothetest.Drytheunderarmareaandthenimmediatelypaintitwithiodinesolution.Allowtheareatodry,thenlightlysprinkletheareawithstarchpowder.Gentlyblowoffanyexcessstarchpowder.Thehyperhidroticareawilldevelopadeepblue-blackcoloroverapproximately10minutes.

Eachinjectionsitehasaringofeffectofuptoapproximately2cmindiameter.Tominimizetheareaofnoeffect,theinjectionsitesshouldbeevenlyspacedasshowninFigure2.

Eachdoseisinjectedtoadepthofapproximately2mmandata45°angletotheskinsurface,withthebevelsideuptominimizeleakageandtoensuretheinjectionsremainintradermal.Ifinjectionsitesaremarkedinink,donotinjectBOTOXdirectlythroughtheinkmarktoavoidapermanenttattooeffect.

2.8 BlepharospasmForblepharospasm,reconstitutedBOTOXisinjectedusingasterile,27-30gaugeneedlewithoutelectromyographicguidance.Theinitialrecommendeddoseis1.25Units-2.5Units(0.05mLto0.1mLvolumeateachsite)injectedintothemedialandlateralpre-tarsalorbicularisoculioftheupperlidandintothelateralpre-tarsalorbicularisoculiofthelowerlid.Avoidinginjectionnearthelevatorpalpebraesuperiorismayreducethecomplicationofptosis.Avoidingmediallowerlidinjections,andtherebyreducingdiffusionintotheinferioroblique,mayreducethecomplicationofdiplopia.Ecchymosisoccurseasilyinthesofteyelidtissues.Thiscanbepreventedbyapplyingpressureattheinjectionsiteimmediatelyaftertheinjection.

Therecommendeddilutiontoachieve1.25Unitsis100Units/8mL;for2.5Unitsitis100Units/4mL(seeTable1).

Ingeneral,theinitialeffectoftheinjectionsisseenwithinthreedaysandreachesapeakatonetotwoweekspost-treatment.Eachtreatmentlastsapproximatelythreemonths,followingwhichtheprocedurecanberepeated.Atrepeattreatmentsessions,thedosemaybeincreaseduptotwo-foldiftheresponsefromtheinitialtreatmentisconsideredinsufficient,usuallydefinedasaneffectthatdoesnotlastlongerthantwomonths.However,thereappearstobelittlebenefitobtainablefrominjectingmorethan5Unitspersite.SometolerancemaybefoundwhenBOTOXisusedintreatingblepharospasmiftreatmentsaregivenanymorefrequentlythaneverythreemonths,andisraretohavetheeffectbepermanent.

ThecumulativedoseofBOTOXtreatmentforblepharospasmina30-dayperiodshouldnotexceed200Units.

2.9 StrabismusBOTOXisintendedforinjectionintoextraocularmusclesutilizingtheelectricalactivityrecordedfromthetipoftheinjectionneedleasaguidetoplacementwithinthetargetmuscle.Injectionwithoutsurgicalexposureorelectromyographicguidanceshouldnotbeattempted.Physiciansshouldbefamiliarwithelectromyographictechnique.

TopreparetheeyeforBOTOXinjection,itisrecommendedthatseveraldropsofalocalanestheticandanoculardecongestantbegivenseveralminutespriortoinjection.

ThevolumeofBOTOXinjectedfortreatmentofstrabismusshouldbebetween0.05-0.15mLpermuscle.

TheinitiallisteddosesofthereconstitutedBOTOX[see Dosage and Administration (2.2)]typicallycreateparalysisoftheinjectedmusclesbeginningonetotwodaysafterinjectionandincreasinginintensityduringthefirstweek.Theparalysislastsfor2-6weeksandgraduallyresolvesoverasimilartimeperiod.Overcorrectionslastingoversixmonthshavebeenrare.Aboutonehalfofpatientswillrequiresubsequentdosesbecauseofinadequateparalyticresponseofthemuscletotheinitialdose,orbecauseofmechanicalfactorssuchaslargedeviationsorrestrictions,orbecauseofthelackofbinocularmotorfusiontostabilizethealignment.

Initial doses in Units Usethelowerlisteddosesfortreatmentofsmalldeviations.Usethelargerdosesonlyforlargedeviations.

• Forverticalmuscles,andforhorizontalstrabismusoflessthan20prismdiopters:1.25Units-2.5Unitsinanyonemuscle.

• Forhorizontalstrabismusof20prismdioptersto50prismdiopters:2.5Units-5Unitsinanyonemuscle.

• ForpersistentVInervepalsyofonemonthorlongerduration:1.25Units-2.5Unitsinthemedialrectusmuscle.

Subsequent doses for residual or recurrent strabismus • Itisrecommendedthatpatientsbere-examined7-14daysafter

eachinjectiontoassesstheeffectofthatdose.

• Patientsexperiencingadequateparalysisofthetargetmusclethatrequiresubsequentinjectionsshouldreceiveadosecomparabletotheinitialdose.

• Subsequentdosesforpatientsexperiencingincompleteparalysisofthetargetmusclemaybeincreaseduptotwo-foldcomparedtothepreviouslyadministereddose.

• Subsequentinjectionsshouldnotbeadministereduntiltheeffectsofthepreviousdosehavedissipatedasevidencedbysubstantialfunctionintheinjectedandadjacentmuscles.

Figure 2: Injection Pattern for Primary Axillary Hyperhidrosis

• Themaximumrecommendeddoseasasingleinjectionforanyonemuscleis25Units.

Therecommendeddilutiontoachieve1.25Unitsis100Units/8mL;for2.5Unitsitis100Units/4mL(seeTable1).

3 DOSAGE FORMS AND STRENGTHSSingle-use,sterile100Unitsor200Unitsvacuum-driedpowderforreconstitutiononlywithsterile,non-preserved0.9%SodiumChlorideInjectionUSPpriortoinjection.

4 CONTRAINDICATIONS4.1 Known Hypersensitivity to Botulinum ToxinBOTOXiscontraindicatedinpatientswhoarehypersensitivetoanybotulinumtoxinpreparationortoanyofthecomponentsintheformulation[see Warnings and Precautions (5.4)].

4.2 Infection at the Injection Site(s)BOTOXiscontraindicatedinthepresenceofinfectionattheproposedinjectionsite(s).

4.3 Acute Urinary Tract Infection and/or Acute Urinary RetentionIntradetrusorinjectionofBOTOXiscontraindicatedinpatientswithdetrusoroveractivityassociatedwithaneurologicconditionwhohaveacuteurinarytractinfection,andinpatientswithacuteurinaryretentionwhoarenotroutinelyperformingcleanintermittentself-catheterization(CIC).

5 WARNINGS AND PRECAUTIONS5.1 Lack of Interchangeability between Botulinum Toxin ProductsThe potency Units of BOTOX are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see Dosage and Administration (2.1), Description (11)].

5.2 Spread of Toxin EffectPostmarketingsafetydatafromBOTOXandotherapprovedbotulinumtoxinssuggestthatbotulinumtoxineffectsmay,insomecases,beobservedbeyondthesiteoflocalinjection.Thesymptomsareconsistentwiththemechanismofactionofbotulinumtoxinandmayincludeasthenia,generalizedmuscleweakness,diplopia,ptosis,dysphagia,dysphonia,dysarthria,urinaryincontinence,andbreathingdifficulties.Thesesymptomshavebeenreportedhourstoweeksafterinjection.Swallowingandbreathingdifficultiescanbelifethreateningandtherehavebeenreportsofdeathrelatedtospreadoftoxineffects.Theriskofsymptomsisprobablygreatestinchildrentreatedforspasticitybutsymptomscanalsooccurinadultstreatedforspasticityandotherconditions,andparticularlyinthosepatientswhohaveanunderlyingconditionthatwouldpredisposethemtothesesymptoms.Inunapproveduses,includingspasticityinchildren,andinapprovedindications,symptomsconsistentwithspreadoftoxineffecthavebeenreportedatdosescomparabletoorlowerthandosesusedtotreatcervicaldystonia.Patientsorcaregiversshouldbeadvisedtoseekimmediatemedicalcareifswallowing,speechorrespiratorydisordersoccur.

NodefinitiveseriousadverseeventreportsofdistantspreadoftoxineffectassociatedwithdermatologicuseofBOTOX/BOTOX®Cosmeticatthelabeleddoseof20Units(forglabellarlines)or100Units(forsevereprimaryaxillaryhyperhidrosis)havebeenreported.

NodefinitiveseriousadverseeventreportsofdistantspreadoftoxineffectassociatedwithBOTOXforblepharospasmattherecommendeddose(30Unitsandbelow),strabismus,orforchronicmigraineatthelabeleddoseshavebeenreported.

5.3 Injections In or Near Vulnerable Anatomic StructuresCareshouldbetakenwheninjectinginornearvulnerableanatomicstructures.SeriousadverseeventsincludingfataloutcomeshavebeenreportedinpatientswhohadreceivedBOTOXinjecteddirectlyintosalivaryglands,theoro-lingual-pharyngealregion,esophagusandstomach.Somepatientshadpre-existingdysphagiaorsignificantdebility.(Safetyandeffectivenesshavenotbeenestablishedforindicationspertainingtotheseinjectionsites.)PneumothoraxassociatedwithinjectionprocedurehasbeenreportedfollowingtheadministrationofBOTOXnearthethorax.Cautioniswarrantedwheninjectinginproximitytothelung,particularlytheapices.

5.4 Hypersensitivity ReactionsSeriousand/orimmediatehypersensitivityreactionshavebeenreported.Thesereactionsincludeanaphylaxis,serumsickness,urticaria,softtissueedema,anddyspnea.Ifsuchareactionoccurs,furtherinjectionofBOTOXshouldbediscontinuedandappropriatemedicaltherapyimmediatelyinstituted.Onefatalcaseofanaphylaxishasbeenreportedinwhichlidocainewasusedasthediluent,andconsequentlythecausalagentcannotbereliablydetermined.

5.5 Dysphagia and Breathing Difficulties in Treatment of Cervical Dystonia

TreatmentwithBOTOXandotherbotulinumtoxinproductscanresultinswallowingorbreathingdifficulties.Patientswithpre-existingswallowingorbreathingdifficultiesmaybemoresusceptibletothesecomplications.Inmostcases,thisisaconsequenceofweakeningofmusclesintheareaofinjectionthatareinvolvedinbreathingorswallowing.Whendistanteffectsoccur,additionalrespiratorymusclesmaybeinvolved[see Warnings and Precautions (5.2)].

Deathsasacomplicationofseveredysphagiahavebeenreportedaftertreatmentwithbotulinumtoxin.Dysphagiamaypersistforseveralmonths,andrequireuseofafeedingtubetomaintainadequatenutritionandhydration.Aspirationmayresultfromseveredysphagiaandisaparticularriskwhentreatingpatientsinwhomswallowingorrespiratoryfunctionisalreadycompromised.

Treatmentofcervicaldystoniawithbotulinumtoxinsmayweakenneckmusclesthatserveasaccessorymusclesofventilation.Thismayresultinacriticallossofbreathingcapacityinpatientswithrespiratorydisorderswhomayhavebecomedependentupontheseaccessorymuscles.Therehavebeenpostmarketingreportsofseriousbreathingdifficulties,includingrespiratoryfailure,incervicaldystoniapatients.

Patientswithsmallerneckmusclemassandpatientswhorequirebilateralinjectionsintothesternocleidomastoidmusclehavebeenreportedtobeatgreaterriskfordysphagia.Limitingthedoseinjectedintothesternocleidomastoidmusclemayreducetheoccurrenceofdysphagia.Injectionsintothelevatorscapulaemaybeassociatedwithanincreasedriskofupperrespiratoryinfectionanddysphagia.

Patientstreatedwithbotulinumtoxinmayrequireimmediatemedicalattentionshouldtheydevelopproblemswithswallowing,speechorrespiratorydisorders.Thesereactionscanoccurwithinhourstoweeksafterinjectionwithbotulinumtoxin[see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

5.6 Pre-Existing Neuromuscular DisordersIndividualswithperipheralmotorneuropathicdiseases,amyotrophiclateralsclerosisorneuromuscularjunctiondisorders(e.g.,myastheniagravisorLambert-Eatonsyndrome)shouldbemonitoredparticularlycloselywhengivenbotulinumtoxin.PatientswithneuromusculardisordersmaybeatincreasedriskofclinicallysignificanteffectsincludingseveredysphagiaandrespiratorycompromisefromtherapeuticdosesofBOTOX [see Adverse Reactions (6.1)].

5.7 Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity associated with a Neurologic Condition

PatientswithcompromisedrespiratorystatustreatedwithBOTOXforupperlimbspasticityshouldbemonitoredclosely.Inadouble-blind,placebo-controlled,parallelgroupstudyinpatientswithstablereducedpulmonaryfunction(definedasFEV140-80%ofpredictedvalueandFEV1/FVC≤0.75),theeventrateinchangeofForcedVitalCapacity≥15%or≥20%wasgenerallygreaterinpatientstreatedwithBOTOXthaninpatientstreatedwithplacebo(seeTable4).

Table 4: Event rate per patient treatment cycle among patients with reduced lung function who experienced at least a 15% or 20% decrease in forced vital capacity from baseline at Week 1, 6, 12 post-injection with up to two treatment cycles with BOTOX or placebo

BOTOX 360 Units

BOTOX240 Units Placebo

≥15% ≥20% ≥15% ≥20% ≥15% ≥20%

Week1 4% 0% 3% 0% 7% 3%

Week6 7% 4% 4% 2% 2% 2%

Week12 10% 5% 2% 1% 4% 1%

Differencesfromplacebowerenotstatisticallysignificant

Inpatientswithreducedlungfunction,upperrespiratorytractinfectionswerealsoreportedmorefrequentlyasadversereactionsinpatientstreatedwithBOTOXthaninpatientstreatedwithplacebo[see Warnings and Precautions (5.10)].

Inanongoingdouble-blind,placebo-controlled,parallelgroupstudyinadultpatientswithdetrusoroveractivityassociatedwithaneurologicconditionandrestrictivelungdiseaseofneuromuscularetiology[definedasFVC50-80%ofpredictedvalueinpatientswithspinalcordinjurybetweenC5andC8,orMS]theeventrateinchangeofForcedVitalCapacity≥15%or≥20%wasgenerallygreaterinpatientstreatedwithBOTOXthaninpatientstreatedwithplacebo(seeTable5).

Table 5: Number and percent of patients experiencing at least a 15% or 20% decrease in FVC from baseline at Week 2, 6, 12 post-injection with BOTOX or placebo

BOTOX 200 Units Placebo

≥15% ≥20% ≥15% ≥20%

Week2 0/12 (0%) 0/12 (0%) 1/11 (9%) 0/11 (0%)

Week6 2/11 (18%) 1/11 (9%) 0/11 (0%) 0/11 (0%)

Week12 0/11 (0%) 0/11 (0%) 0/6 (0%) 0/6 (0%)

5.8 Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm

ReducedblinkingfromBOTOXinjectionoftheorbicularismusclecanleadtocornealexposure,persistentepithelialdefect,andcornealulceration,especiallyinpatientswithVIInervedisorders.Vigoroustreatmentofanyepithelialdefectshouldbeemployed.Thismayrequireprotectivedrops,ointment,therapeuticsoftcontactlenses,orclosureoftheeyebypatchingorothermeans.

5.9 Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus

DuringtheadministrationofBOTOXforthetreatmentofstrabismus,retrobulbarhemorrhagessufficienttocompromiseretinalcirculationhaveoccurred.Itisrecommendedthatappropriateinstrumentstodecompresstheorbitbeaccessible.

5.10 Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity

BronchitiswasreportedmorefrequentlyasanadversereactioninpatientstreatedforupperlimbspasticitywithBOTOX(3%at251Units-360Unitstotaldose),comparedtoplacebo(1%).Inpatientswithreducedlungfunctiontreatedforupperlimbspasticity,upperrespiratorytractinfectionswerealsoreportedmorefrequentlyasadversereactionsinpatientstreatedwithBOTOX(11%at360Unitstotaldose;8%at240Unitstotaldose)comparedtoplacebo(6%).

5.11 Autonomic Dysreflexia and Urinary Retention in Patients Treated for Detrusor Overactivity associated with a Neurologic Condition

AutonomicdysreflexiaassociatedwithintradetrusorinjectionsofBOTOXcouldoccurinpatientstreatedfordetrusoroveractivityassociatedwithaneurologicconditionandmayrequirepromptmedicaltherapy.Inclinicaltrials,theincidenceofautonomicdysreflexiawasgreaterinpatientstreatedwithBOTOX200Unitscomparedwithplacebo(1.5%versus0.4%,respectively).

Indouble-blind,placebo-controlledtrials,theproportionofsubjectswhowerenotusingcleanintermittentcatheterization(CIC)priortoinjectionandwhosubsequentlyrequiredcatheterizationforurinaryretentionfollowingtreatmentwithBOTOXorplaceboisshowninTable6.Thedurationofpost-injectioncatheterizationisalsoshown.

Table 6: Proportion of Patients not using CIC at baseline and then Catheterizing for Urinary Retention and Duration of Catheterization following injection in double-blind, placebo-controlled clinical trials

Timepoint BOTOX 200 Unit (N=108)

Placebo (N=104)

Proportion of Patients Catheterizing for Urinary RetentionAtanytimeduringcompletetreatmentcycle 33(30.6%) 7(6.7%)

Duration of Catheterization for Urinary Retention (Days)Median 289 358Min,Max 1,530 2,379

AmongpatientsnotusingCICatbaseline,thosewithMSweremorelikelytorequireCICpost-injectionthanthosewithSCI(seeTable7).

Table 7: Proportion of Patients by Etiology (MS and SCI) not using CIC at baseline and then Catheterizing for Urinary Retention following injection in double-blind, placebo-controlled clinical trials

Timepoint

MS SCIBOTOX 200 Unit (N=86)

Placebo (N=88)

BOTOX 200 Unit (N=22)

Placebo (N=16)

Atanytimeduringcompletetreatmentcycle 27(31%) 4(5%) 6(27%) 3(19%)

Duetotheriskofurinaryretention,onlypatientswhoarewillingand/orabletoinitiatecatheterizationpost-treatment,ifrequired,shouldbeconsideredfortreatment.

Inpatientswhoarenotcatheterizing,post-voidresidual(PVR)urinevolumeshouldbeassessedwithin2weekspost-treatmentandperiodicallyasmedicallyappropriateupto12weeks.CatheterizationshouldbeinstitutedifPVRurinevolumeexceeds200mLandcontinueduntilPVRfallsbelow200mL.Patientsshouldbeinstructedtocontacttheirphysicianiftheyexperiencedifficultyinvoidingascatheterizationmayberequired.

5.12 Human Albumin and Transmission of Viral DiseasesThisproductcontainsalbumin,aderivativeofhumanblood.Basedoneffectivedonorscreeningandproductmanufacturingprocesses,itcarriesanextremelyremoteriskfortransmissionofviraldiseases.AtheoreticalriskfortransmissionofCreutzfeldt-Jakobdisease(CJD)isalsoconsideredextremelyremote.NocasesoftransmissionofviraldiseasesorCJDhaveeverbeenreportedforalbumin.

6 ADVERSE REACTIONSThefollowingadversereactionstoBOTOX(onabotulinumtoxinA)forinjectionarediscussedingreaterdetailinothersectionsofthelabeling:

• SpreadofToxinEffects[see Warnings and Precautions (5.2)]

• Hypersensitivity[see Contraindications (4.1) and Warnings and Precautions (5.4)]

• DysphagiaandBreathingDifficultiesinTreatmentofCervicalDystonia[see Warnings and Precautions (5.5)]

• BronchitisandUpperRespiratoryTractInfectionsinPatientsTreatedforSpasticity[see Warnings and Precautions (5.10)]

6.1 Clinical Trials ExperienceBecauseclinicaltrialsareconductedunderwidelyvaryingconditions,theadversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinclinicalpractice.

BOTOXandBOTOXCosmeticcontainthesameactiveingredientinthesameformulation,butwithdifferentlabeledIndicationsandUsage.Therefore,adversereactionsobservedwiththeuseofBOTOXCosmeticalsohavethepotentialtobeobservedwiththeuseofBOTOX.Ingeneral,adversereactionsoccurwithinthefirstweekfollowinginjectionofBOTOXandwhilegenerallytransient,mayhaveadurationofseveralmonthsorlonger.Localizedpain,infection,inflammation,tenderness,swelling,erythema,and/orbleeding/bruisingmaybeassociatedwiththeinjection.Needle-relatedpainand/oranxietymayresultinvasovagalresponses(includinge.g.,syncope,hypotension),whichmayrequireappropriatemedicaltherapy.

Localweaknessoftheinjectedmuscle(s)representstheexpectedpharmacologicalactionofbotulinumtoxin.However,weaknessofnearbymusclesmayalsooccurduetospreadoftoxin[see Warnings and Precautions (5.2)].

Detrusor Overactivity associated with a Neurologic ConditionTable8presentsthemostfrequentlyreportedadversereactionsindouble-blind,placebo-controlledstudieswithin12weeksofinjectionfordetrusoroveractivityassociatedwithaneurologiccondition.

Table 8: Adverse Reactions Reported by >2% of BOTOX treated Patients and More Frequent than in Placebo-treated Patients Within the First 12 Weeks after Intradetrusor Injection in Double-blind, Placebo-controlled Clinical Trials

Adverse Reactions by Body SystemsBOTOX

200 Units (N=262)

Placebo (N=272)

Infections and infestations Urinary tract infection 64 (24%) 47 (17%)

Renal and urinary disorders Urinary retention Hematuria

45 (17%) 10 (4%)

8 (3%) 8 (3%)

General disorders and administration site conditions Fatigue 10 (4%) 3 (1%)

Psychiatric disorders Insomnia 4 (2%) 0 (0%)

ThefollowingadverseeventrateswithBOTOX200Unitswerereportedatanytimefollowinginitialinjectionandpriortore-injectionorstudyexit(mediandurationof44weeksofexposure):urinarytractinfections(49%),urinaryretention(17%),fatigue(6%),constipation(4%),muscularweakness(4%),dysuria(4%),fall(3%),gaitdisturbance(3%),insomnia(3%),andmusclespasm(2%).

IntheMSpatientsenrolledinthedouble-blind,placebo-controlledtrials,theMSexacerbationannualizedrate(i.e.,numberofMSexacerbationeventsperpatient-year)was0.23forBOTOXand0.20forplacebo.Nochangewasobservedintheoverallsafetyprofilewithrepeatdosing.

Chronic MigraineIndouble-blind,placebo-controlledchronicmigraineefficacytrials(Study1andStudy2),thediscontinuationratewas12%intheBOTOXtreatedgroupand10%intheplacebo-treatedgroup.Discontinuationsduetoanadverseeventwere4%intheBOTOXgroupand1%intheplacebogroup.ThemostfrequentadverseeventsleadingtodiscontinuationintheBOTOXgroupwereneckpain,headache,worseningmigraine,muscularweaknessandeyelidptosis.

ThemostfrequentlyreportedadversereactionsfollowinginjectionofBOTOXforchronicmigraineappearinTable9.

Table 9: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and More Frequent than in Placebo-treated Patients in Two Chronic Migraine Double-blind, Placebo-controlled Clinical Trials

Adverse Reactions by Body SystemsBOTOX

155 Units-195 Units (N=687)

Placebo (N=692)

Nervous system disorders Headache Migraine Facial paresis

32 (5%) 26 (4%) 15 (2%)

22 (3%) 18 (3%) 0 (0%)

Eye disorders Eyelid ptosis 25 (4%) 2 (< 1%)

Infections and Infestations Bronchitis 17 (3%) 11 (2%)

Musculoskeletal and connective tissue disorders Neck pain Musculoskeletal stiffness Muscular weakness Myalgia Musculoskeletal pain Muscle spasms

60 (9%) 25 (4%) 24 (4%) 21 (3%) 18 (3%) 13 (2%)

19 (3%) 6 (1%)

2 (< 1%) 6 (1%) 10 (1%) 6 (1%)

General disorders and administration site conditions Injection site pain 23 (3%) 14 (2%)

Vascular Disorders Hypertension 11 (2%) 7 (1%)

OtheradversereactionsthatoccurredmorefrequentlyintheBOTOXgroupcomparedtotheplacebogroupatafrequencylessthan1%andpotentiallyBOTOXrelatedinclude:vertigo,dryeye,eyelidedema,dysphagia,eyeinfection,andjawpain.Severeworseningofmigrainerequiringhospitalizationoccurredinapproximately1%ofBOTOXtreatedpatientsinStudy1andStudy2,usuallywithinthefirstweekaftertreatment,comparedto0.3%ofplacebo-treatedpatients.

Upper Limb SpasticityThemostfrequentlyreportedadversereactionsfollowinginjectionofBOTOXforadultspasticityappearinTable10.

Table 10: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and More Frequent than in Placebo-treated Patients in Adult Spasticity Double-blind, Placebo-controlled Clinical Trials

Adverse Reactions by Body System

BOTOX 251 Units- 360 Units (N=115)

BOTOX 150 Units- 250 Units (N=188)

BOTOX <150 Units

(N=54)

Placebo (N=182)

Gastrointestinal disorder Nausea 3 (3%) 3 (2%) 1 (2%) 1 (1%)

General disorders and administration site conditions Fatigue 4 (3%) 4 (2%) 1 (2%) 0

Infections and infestations Bronchitis 4 (3%) 4 (2%) 0 2 (1%)

Musculoskeletal and connective tissue disorders Pain in extremity Muscular weakness

7 (6%) 0

10 (5%) 7 (4%)

5 (9%) 1 (2%)

8 (4%) 2 (1%)

Cervical DystoniaIncervicaldystoniapatientsevaluatedforsafetyindouble-blindandopen-labelstudiesfollowinginjectionofBOTOX,themostfrequentlyreportedadversereactionsweredysphagia(19%),upperrespiratoryinfection(12%),neckpain(11%),andheadache(11%).

Othereventsreportedin2-10%ofpatientsinanyonestudyindecreasingorderofincidenceinclude:increasedcough,flusyndrome,backpain,rhinitis,dizziness,hypertonia,sorenessatinjectionsite,asthenia,oraldryness,speechdisorder,fever,nausea,anddrowsiness.Stiffness,numbness,diplopia,ptosis,anddyspneahavebeenreported.

DysphagiaandsymptomaticgeneralweaknessmaybeattributabletoanextensionofthepharmacologyofBOTOXresultingfromthespreadofthetoxinoutsidetheinjectedmuscles[see Warnings and Precautions (5.2, 5.5)].

ThemostcommonsevereadversereactionassociatedwiththeuseofBOTOXinjectioninpatientswithcervicaldystoniaisdysphagiawithabout20%ofthesecasesalsoreportingdyspnea[see Warnings and Precautions (5.2, 5.5)].Mostdysphagiaisreportedasmildormoderateinseverity.However,itmaybeassociatedwithmoreseveresignsandsymptoms[see Warnings and Precautions (5.5)].

Additionally,reportsintheliteratureincludeacaseofafemalepatientwhodevelopedbrachialplexopathytwodaysafterinjectionof120UnitsofBOTOXforthetreatmentofcervicaldystonia,andreportsofdysphoniainpatientswhohavebeentreatedforcervicaldystonia.

Primary Axillary HyperhidrosisThemostfrequentlyreportedadversereactions(3-10%ofadultpatients)followinginjectionofBOTOXindouble-blindstudiesincludedinjectionsitepainandhemorrhage,non-axillarysweating,infection,pharyngitis,flusyndrome,headache,fever,neckorbackpain,pruritus,andanxiety.

Thedatareflect346patientsexposedtoBOTOX50Unitsand110patientsexposedtoBOTOX75Unitsineachaxilla.BlepharospasmInastudyofblepharospasmpatientswhoreceivedanaveragedosepereyeof33Units(injectedat3to5sites)ofthecurrentlymanufacturedBOTOX,themostfrequentlyreportedadversereactionswereptosis(21%),superficialpunctatekeratitis(6%),andeyedryness(6%).

Othereventsreportedinpriorclinicalstudiesindecreasingorderofincidenceinclude:irritation,tearing,lagophthalmos,photophobia,ectropion,keratitis,diplopia,entropion,diffuseskinrash,andlocalswellingoftheeyelidskinlastingforseveraldaysfollowingeyelidinjection.

IntwocasesofVIInervedisorder,reducedblinkingfromBOTOXinjectionoftheorbicularismuscleledtoseriouscornealexposure,persistentepithelialdefect,cornealulcerationandacaseofcornealperforation.Focalfacialparalysis,syncope,andexacerbationofmyastheniagravishavealsobeenreportedaftertreatmentofblepharospasm.

StrabismusExtraocularmusclesadjacenttotheinjectionsitecanbeaffected,causingverticaldeviation,especiallywithhigherdosesofBOTOX.Theincidenceratesoftheseadverseeffectsin2058adultswhoreceivedatotalof3650injectionsforhorizontalstrabismuswas17%.

Theincidenceofptosishasbeenreportedtobedependentonthelocationoftheinjectedmuscles,1%afterinferiorrectusinjections,16%afterhorizontalrectusinjectionsand38%aftersuperiorrectusinjections.

Inaseriesof5587injections,retrobulbarhemorrhageoccurredin0.3%ofcases.

6.2 ImmunogenicityAswithalltherapeuticproteins,thereisapotentialforimmunogenicity.FormationofneutralizingantibodiestobotulinumtoxintypeAmayreducetheeffectivenessofBOTOXtreatmentbyinactivatingthebiologicalactivityofthetoxin.

Inalongterm,open-labelstudyevaluating326cervicaldystoniapatientstreatedforanaverageof9treatmentsessionswiththecurrentformulationofBOTOX,4(1.2%)patientshadpositiveantibodytests.All4ofthesepatientsrespondedtoBOTOXtherapyatthetimeofthepositiveantibodytest.However,3ofthesepatientsdevelopedclinicalresistanceaftersubsequenttreatment,whilethefourthpatientcontinuedtorespondtoBOTOXtherapyfortheremainderofthestudy.

Onepatientamongthe445hyperhidrosispatients(0.2%),twopatientsamongthe380adultupperlimbspasticitypatients(0.5%),nopatientsamong406migrainepatients,andnopatientsamong475detrusoroveractivityassociatedwithaneurologicconditionpatientswithanalyzedspecimensdevelopedthepresenceofneutralizingantibodies.

ThedatareflectthepatientswhosetestresultswereconsideredpositiveornegativeforneutralizingactivitytoBOTOXinamouseprotectionassay.Theresultsofthesetestsarehighlydependentonthesensitivityandspecificityoftheassay.Forthesereasons,comparisonoftheincidenceofneutralizingactivitytoBOTOXwiththeincidencereportedtootherproductsmaybemisleading.

Thecriticalfactorsforneutralizingantibodyformationhavenotbeenwellcharacterized.TheresultsfromsomestudiessuggestthatBOTOXinjectionsatmorefrequentintervalsorathigherdosesmayleadtogreaterincidenceofantibodyformation.Thepotentialforantibodyformationmaybeminimizedbyinjectingwiththelowesteffectivedosegivenatthelongestfeasibleintervalsbetweeninjections.

6.3 Post-Marketing ExperienceTherehavebeenspontaneousreportsofdeath,sometimesassociatedwithdysphagia,pneumonia,and/orothersignificantdebilityoranaphylaxis,aftertreatmentwithbotulinumtoxin[see Warnings and Precautions (5.4, 5.5)].

Therehavealsobeenreportsofadverseeventsinvolvingthecardiovascularsystem,includingarrhythmiaandmyocardialinfarction,somewithfataloutcomes.Someofthesepatientshadriskfactorsincludingcardiovasculardisease.Theexactrelationshipoftheseeventstothebotulinumtoxininjectionhasnotbeenestablished.

Newonsetorrecurrentseizureshavealsobeenreported,typicallyinpatientswhoarepredisposedtoexperiencingtheseevents.Theexactrelationshipoftheseeventstothebotulinumtoxininjectionhasnotbeenestablished.

ThefollowingadverseeventshavebeenidentifiedduringpostapprovaluseofBOTOX:abdominalpain;anorexia;brachialplexopathy;diarrhea;dyspnea;facialpalsy;facialparesis;hyperhidrosis;hypoacusis;hypoaesthesia;localizednumbness;malaise;muscleweakness;myalgia;paresthesia;pyrexia;radiculopathy;skinrash(includingerythemamultiforme,andpsoriasiformeruption);tinnitus;vertigo;visualdisturbances;andvomiting.

Becausetheseeventsarereportedvoluntarilyfromapopulationofuncertainsize,itisnotalwayspossibletoreliablyestimatetheirfrequencyorestablishacausalrelationshiptodrugexposure.

7 DRUG INTERACTIONSNoformaldruginteractionstudieshavebeenconductedwithBOTOX(onabotulinumtoxinA)forinjection.

Co-administrationofBOTOXandaminoglycosidesorotheragentsinterferingwithneuromusculartransmission(e.g.,curare-likecompounds)shouldonlybeperformedwithcautionastheeffectofthetoxinmaybepotentiated.

UseofanticholinergicdrugsafteradministrationofBOTOXmaypotentiatesystemicanticholinergiceffects.

Theeffectofadministeringdifferentbotulinumneurotoxinproductsatthesametimeorwithinseveralmonthsofeachotherisunknown.Excessiveneuromuscularweaknessmaybeexacerbatedbyadministrationofanotherbotulinumtoxinpriortotheresolutionoftheeffectsofapreviouslyadministeredbotulinumtoxin.

ExcessiveweaknessmayalsobeexaggeratedbyadministrationofamusclerelaxantbeforeorafteradministrationofBOTOX.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancyCategoryC.

Therearenoadequateandwell-controlledstudiesinpregnantwomen.BOTOXshouldbeusedduringpregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.

WhenBOTOX(4,8,or16Units/kg)wasadministeredintramuscularlytopregnantmiceorratstwotimesduringtheperiodoforganogenesis(ongestationdays5and13),reductionsinfetalbodyweightanddecreasedfetalskeletalossificationwereobservedatthetwohighestdoses.Theno-effectdosefordevelopmentaltoxicityinthesestudies(4Units/kg)isapproximately1½timestheaveragehighhumandoseforupperlimbspasticityof360Unitsonabodyweightbasis(Units/kg).

WhenBOTOXwasadministeredintramuscularlytopregnantrats(0.125,0.25,0.5,1,4,or8Units/kg)orrabbits(0.063,0.125,0.25,or0.5Units/kg)dailyduringtheperiodoforganogenesis(totalof12dosesinrats,13dosesinrabbits),reducedfetalbodyweightsanddecreasedfetalskeletalossificationwereobservedatthetwohighestdosesinratsandatthehighestdoseinrabbits.Thesedoseswerealsoassociatedwithsignificantmaternaltoxicity,includingabortions,earlydeliveries,andmaternaldeath.Thedevelopmentalno-effectdosesinthesestudiesof1Unit/kginratsand0.25Units/kginrabbitsarelessthantheaveragehighhumandosebasedonUnits/kg.

Whenpregnantratsreceivedsingleintramuscularinjections(1,4,or16Units/kg)atthreedifferentperiodsofdevelopment(priortoimplantation,implantation,ororganogenesis),noadverseeffectsonfetaldevelopmentwereobserved.Thedevelopmentalno-effectlevelforasinglematernaldoseinrats(16Units/kg)isapproximately3timestheaveragehighhumandosebasedonUnits/kg.

8.3 Nursing MothersItisnotknownwhetherBOTOXisexcretedinhumanmilk.Becausemanydrugsareexcretedinhumanmilk,cautionshouldbeexercisedwhenBOTOXisadministeredtoanursingwoman.

8.4 Pediatric UseUrinary Incontinence due to Detrusor Overactivity associated with a Neurologic ConditionSafetyandeffectivenessinpatientsbelowtheageof18yearshavenotbeenestablished.

Prophylaxis of Headaches in Chronic MigraineSafetyandeffectivenessinpatientsbelowtheageof18yearshavenotbeenestablished.

SpasticitySafetyandeffectivenessinpatientsbelowtheageof18yearshavenotbeenestablished.

Axillary HyperhidrosisSafetyandeffectivenessinpatientsbelowtheageof18yearshavenotbeenestablished.

Cervical DystoniaSafetyandeffectivenessinpediatricpatientsbelowtheageof16yearshavenotbeenestablished.

Blepharospasm and StrabismusSafetyandeffectivenessinpediatricpatientsbelowtheageof12yearshavenotbeenestablished.

8.5 Geriatric UseClinicalstudiesofBOTOXdidnotincludesufficientnumbersofsubjectsaged65andovertodeterminewhethertheyresponddifferentlyfromyoungersubjects.Otherreportedclinicalexperiencehasnotidentifieddifferencesinresponsesbetweentheelderlyandyoungerpatients.Thereweretoofewpatientsovertheageof75toenableanycomparisons.Ingeneral,doseselectionforanelderlypatientshouldbecautious,usuallystartingatthelowendofthedosingrange,reflectingthegreaterfrequencyofdecreasedhepatic,renal,orcardiacfunction,andofconcomitantdiseaseorotherdrugtherapy.

10 OVERDOSAGEExcessivedosesofBOTOX(onabotulinumtoxinA)forinjectionmaybeexpectedtoproduceneuromuscularweaknesswithavarietyofsymptoms.

Symptomsofoverdosearelikelynottobepresentimmediatelyfollowinginjection.Shouldaccidentalinjectionororalingestionoccuroroverdosebesuspected,thepersonshouldbemedicallysupervisedforseveralweeksforsignsandsymptomsofsystemicmuscularweaknesswhichcouldbelocal,ordistantfromthesiteofinjection[see Boxed Warning and Warnings and Precautions (5.2, 5.5)].

Ifthemusculatureoftheoropharynxandesophagusareaffected,aspirationmayoccurwhichmayleadtodevelopmentofaspirationpneumonia.Iftherespiratorymusclesbecomeparalyzedorsufficientlyweakened,intubationandassistedrespirationmaybenecessaryuntilrecoverytakesplace.Supportivecarecouldinvolvetheneedforatracheostomyand/orprolongedmechanicalventilation,inadditiontoothergeneralsupportivecare.

Thesepatientsshouldbeconsideredforfurthermedicalevaluationandappropriatemedicaltherapyimmediatelyinstituted,whichmayincludehospitalization.

Intheeventofoverdose,antitoxinraisedagainstbotulinumtoxinisavailablefromtheCentersforDiseaseControlandPrevention(CDC)inAtlanta,GA.However,theantitoxinwillnotreverseanybotulinumtoxin-inducedeffectsalreadyapparentbythetimeofantitoxinadministration.Intheeventofsuspectedoractualcasesofbotulinumtoxinpoisoning,pleasecontactyourlocalorstateHealthDepartmenttoprocessarequestforantitoxinthroughtheCDC.Ifyoudonotreceivearesponsewithin30minutes,pleasecontacttheCDCdirectlyat1-770-488-7100.Moreinformationcanbeobtainedathttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm.

11 DESCRIPTIONBOTOX(onabotulinumtoxinA)forinjectionisasterile,vacuum-driedpurifiedbotulinumtoxintypeA,producedfromfermentationofHallstrainClostridiumbotulinumtypeA,andintendedforintramuscular,intradetrusorandintradermaluse.Itispurifiedfromtheculturesolutionbydialysisandaseriesofacidprecipitationstoacomplexconsistingoftheneurotoxin,andseveralaccessoryproteins.ThecomplexisdissolvedinsterilesodiumchloridesolutioncontainingAlbuminHumanandissterilefiltered(0.2microns)priortofillingandvacuum-drying.

TheprimaryreleaseprocedureforBOTOX usesacell-basedpotencyassaytodeterminethepotencyrelativetoareferencestandard.TheassayisspecifictoAllergan’sproductsBOTOXandBOTOXCosmetic.OneUnitofBOTOXcorrespondstothecalculatedmedianintraperitoneallethaldose(LD50)inmice.Duetospecificdetailsofthisassaysuchasthevehicle,dilutionscheme,andlaboratoryprotocols,UnitsofbiologicalactivityofBOTOXcannotbecomparedtonorconvertedintoUnitsofanyotherbotulinumtoxinoranytoxinassessedwithanyotherspecificassaymethod.ThespecificactivityofBOTOXisapproximately20Units/nanogramofneurotoxinproteincomplex.

EachvialofBOTOXcontainseither100UnitsofClostridiumbotulinumtypeAneurotoxincomplex,0.5mgofAlbuminHuman,and0.9mgofsodiumchloride;or200UnitsofClostridiumbotulinumtypeAneurotoxincomplex,1mgofAlbuminHuman,and1.8mgofsodiumchlorideinasterile,vacuum-driedformwithoutapreservative.

12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionBOTOXblocksneuromusculartransmissionbybindingtoacceptorsitesonmotororsympatheticnerveterminals,enteringthenerveterminals,andinhibitingthereleaseofacetylcholine.ThisinhibitionoccursastheneurotoxincleavesSNAP-25,aproteinintegraltothesuccessfuldockingandreleaseofacetylcholinefromvesiclessituatedwithinnerveendings.Wheninjectedintramuscularlyattherapeuticdoses,BOTOX producespartialchemicaldenervationofthemuscleresultinginalocalizedreductioninmuscleactivity.Inaddition,themusclemayatrophy,axonalsproutingmayoccur,andextrajunctionalacetylcholinereceptorsmaydevelop.Thereisevidencethatreinnervationofthemusclemayoccur,thusslowlyreversingmuscledenervationproducedbyBOTOX.Wheninjectedintradermally,BOTOXproducestemporarychemicaldenervationofthesweatglandresultinginlocalreductioninsweating.

Followingintradetrusorinjection,BOTOXaffectstheefferentpathwaysofdetrusoractivityviainhibitionofacetylcholinerelease.Inaddition,BOTOXisbelievedtoinhibitafferentneurotransmittersandsensorypathways.

12.3 PharmacokineticsUsingcurrentlyavailableanalyticaltechnology,itisnotpossibletodetectBOTOXintheperipheralbloodfollowingintramuscularinjectionattherecommendeddoses.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisLongtermstudiesinanimalshavenotbeenperformedtoevaluatethecarcinogenicpotentialofBOTOX.MutagenesisBOTOXwasnegativeinabatteryofinvitro(microbialreversemutationassay,mammaliancellmutationassay,andchromosomalaberrationassay)andinvivo(micronucleusassay)genetictoxicologicassays.

Impairment of FertilityInfertilitystudiesofBOTOX(4,8,or16Units/kg)inwhicheithermaleorfemaleratswereinjectedintramuscularlypriortomatingandonthedayofmating(3doses,2weeksapartformales,2doses,2weeksapartforfemales)tountreatedanimals,reducedfertilitywasobservedinmalesattheintermediateandhighdosesandinfemalesatthehighdose.Theno-effectdosesforreproductivetoxicity(4Units/kginmales,8Units/kginfemales)areapproximatelyequaltotheaveragehighhumandoseforupperlimbspasticityof360Unitsonabodyweightbasis(Units/kg).

13.2 Animal ToxicologyInastudytoevaluateinadvertentperibladderadministration,bladderstoneswereobservedin1of4malemonkeysthatwereinjectedwithatotalof6.8Units/kgdividedintotheprostaticurethraandproximalrectum(singleadministration).Nobladderstoneswereobservedinmaleorfemalemonkeysfollowinginjectionofupto36Units/kg(~12Xthehumandose)directlytothebladderaseithersingleor4repeatdoseinjectionsorinfemaleratsforsingleinjectionsupto100Units/kg(~33Xthehumandose).

14 CLINICAL STUDIES14.1 Detrusor Overactivity associated with a Neurologic ConditionTwodouble-blind,placebo-controlled,randomized,multi-centerclinicalstudieswereconductedinpatientswithurinaryincontinenceduetodetrusoroveractivityassociatedwithaneurologicconditionwhowereeitherspontaneouslyvoidingorusingcatheterization.Atotalof691spinalcordinjury(T1orbelow)ormultiplesclerosispatients,whohadaninadequateresponsetoorwereintolerantofatleastoneanticholinergicmedication,wereenrolled.Thesepatientswererandomizedtoreceiveeither200UnitsofBOTOX(n=227),300UnitsofBOTOX(n=223),orplacebo(n=241).Inbothstudies,significantimprovementscomparedtoplacebointheprimaryefficacyvariableofchangefrombaselineinweeklyfrequencyofincontinenceepisodeswereobservedforBOTOX(200Units)attheprimaryefficacytimepointatweek6.Increasesinmaximumcystometriccapacityandreductionsinmaximumdetrusorpressureduringthefirstinvoluntarydetrusorcontractionwerealsoobserved.TheseprimaryandsecondaryendpointsareshowninTables11and12,andFigures3and4.

NoadditionalbenefitofBOTOX300Unitsover200Unitswasdemonstrated.

Table 11: Key Primary and Secondary Endpoints at Baseline and Change from Baseline in Study 1

BOTOX 200 Units Placebo Treatment

Difference* p-value*

Weekly Frequency of Urinary Incontinence Episodesa

NMean BaselineMean Change* at Week 2Mean Change* at Week 6**

Mean Change* at Week 12

13432.3-15.3-19.9

-19.8

14628.3-10.0-10.6

-8.8

-5.3-9.2

(-13.1,-5.3)-11.0

–p<0.001

–

Maximum Cystometric Capacityb (mL)

NMean BaselineMean Change* at Week 6**

123253.8135.9

129259.112.1

123.9(89.1,158.7)

p<0.001

Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O)

NMean BaselineMean Change* at Week 6**

4163.1-28.1

10357.4-3.7

-24.4

–

*Meanchange,treatmentdifferenceandp-valuearebasedonaLOCFanalysisusinganANCOVAmodelwithbaselineweeklyendpointascovariateandtreatmentgroup,etiologyatstudyentry(spinalcordinjuryormultiplesclerosis),concurrentanticholinergictherapyatscreening,andinvestigatorasfactors.

**PrimaryTimepointaPrimaryendpointbSecondaryendpoint

Table 12: Key Primary and Secondary Endpoints at Baseline and Change from Baseline in Study 2

BOTOX 200 Units Placebo Treatment

Difference* p-value*

Weekly Frequency of Urinary Incontinence Episodesa

NMean BaselineMean Change* at Week 2Mean Change* at Week 6**

Mean Change* at Week 12

9132.7-18.0-19.6

-19.6

9136.8-7.9-10.8

-10.7

-10.1-8.8

(-14.5,-3.0)-8.9

–p=0.003

–

Maximum Cystometric Capacityb (mL)

NMean BaselineMean Change* at Week 6**

88239.6150.8

85253.82.8

148.0(101.8,194.2)

p<0.001

Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O)

NMean BaselineMean Change* at Week 6**

2965.6-28.7

6843.72.1

-30.7

–

*Meanchange,treatmentdifferenceandp-valuearebasedonaLOCFanalysisusinganANCOVAmodelwithbaselineweeklyendpointascovariateandtreatmentgroup,etiologyatstudyentry(spinalcordinjuryormultiplesclerosis),concurrentanticholinergictherapyatscreening,andinvestigatorasfactors.

**PrimaryTimepointaPrimaryendpointbSecondaryendpoint

Figure 3: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study 1

Figure 4: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study 2

Themediandurationofresponseinthetwopivotalstudies,basedonpatientqualificationforre-treatmentwas295-337days(42-48weeks)forthe200Unitdosegroupcomparedto96-127days(13-18weeks)forplacebo.Re-treatmentwasbasedonlossofeffectonincontinenceepisodefrequency(50%ofeffectinstudy1;70%ofeffectinstudy2).

14.2 Chronic MigraineBOTOXwasevaluatedintworandomized,multi-center,24-week,2injectioncycle,placebo-controlleddouble-blindstudies.Study1andStudy2includedchronicmigraineadultswhowerenotusinganyconcurrentheadacheprophylaxis,andduringa28-daybaselineperiodhad≥15headachedayslasting4hoursormore,with≥50%beingmigraine/probablemigraine.Inbothstudies,patientswererandomizedtoreceiveplaceboor155Unitsto195UnitsBOTOXinjectionsevery12weeksforthe2-cycle,double-blindphase.Patientswereallowedtouseacuteheadachetreatmentsduringthestudy.BOTOXtreatmentdemonstratedstatisticallysignificantandclinicallymeaningfulimprovementsfrombaselinecomparedtoplaceboforkeyefficacyvariables(seeTable13).

Table 13: Week 24 Key Efficacy Variables for Study 1 and Study 2

Efficacy per 28 days

Study 1 Study 2

BOTOX (N=341)

Placebo (N=338)

BOTOX (N=347)

Placebo (N=358)

Change from baseline in frequency of headache days -7.8* -6.4 -9.2* -6.9

Change from baseline in total cumulative hours of headache on headache days

-107* -70 -134* -95

*Significantlydifferentfromplacebo(p≤0.05)

PatientstreatedwithBOTOXhadasignificantlygreatermeandecreasefrombaselineinthefrequencyofheadachedaysatmosttimepointsfromWeek4toWeek24inStudy1(Figure5),andalltimepointsfromWeek4toWeek24inStudy2(Figure6),comparedtoplacebo-treatedpatients.

Figure 5: Mean Change from Baseline in Number of Headache Days for Study 1

Figure 6: Mean Change from Baseline in Number of Headache Days for Study 2

14.3 Upper Limb SpasticityTheefficacyandsafetyofBOTOXforthetreatmentofupperlimbspasticitywereevaluatedinthreerandomized,multi-center,double-blind,placebo-controlledstudies.

Study1included126patients(64BOTOXand62placebo)withupperlimbspasticity(Ashworthscoreofatleast3forwristflexortoneandatleast2forfingerflexortone)whowereatleast6monthspost-stroke.BOTOX(atotaldoseof200Unitsto240Units)andplacebowereinjectedintramuscularly(IM)intotheflexordigitorumprofundus,flexordigitorumsublimis,flexorcarpiradialis,flexorcarpiulnaris,andifnecessaryintotheadductorpollicisandflexorpollicislongus(seeTable14).UseofanEMG/nervestimulatorwasrecommendedtoassistinpropermusclelocalizationforinjection.Patientswerefollowedfor12weeks.

Table 14: Study Medication Dose and Injection Sites in Study 1

Muscles Injected Volume (mL)

BOTOX (Units)

Number of Injection Sites

Wrist Flexor Carpi Radialis 1 50 1

Flexor Carpi Ulnaris 1 50 1

Finger Flexor Digitorum Profundus 1 50 1

Flexor Digitorum Sublimis 1 50 1

Thumb Adductor Pollicisa 0.4 20 1

Flexor Pollicis Longusa 0.4 20 1

ainjectedonlyifspasticityispresentinthismuscle

Theprimaryefficacyvariablewaswristflexorsmuscletoneatweek6,asmeasuredbytheAshworthscore.TheAshworthScaleisaclinicalmeasureoftheforcerequiredtomoveanextremityaroundajoint,withareductioninscoreclinicallyrepresentingareductionintheforceneededtomoveajoint(i.e.,improvementinspasticity).

Possiblescoresrangefrom0to4:

0=Noincreaseinmuscletone(none)

1=Slightincreaseinmuscletone,givinga‘catch’whenthelimbwasmovedinflexionorextension(mild)

2=Moremarkedincreaseinmuscletonebutaffectedlimbiseasilyflexed(moderate)

3=Considerableincreaseinmuscletone-passivemovementdifficult(severe)

4=Limbrigidinflexionorextension(verysevere).

KeysecondaryendpointsincludedPhysicianGlobalAssessment,fingerflexorsmuscletone,andthumbflexorstoneatWeek6.ThePhysicianGlobalAssessmentevaluatedtheresponsetotreatmentintermsofhowthepatientwasdoinginhis/herlifeusingascalefrom-4=verymarkedworseningto+4=verymarkedimprovement.Study1resultsontheprimaryendpointandthekeysecondaryendpointsareshowninTable15.

Table 15: Primary and Key Secondary Endpoints by Muscle Group at Week 6 in Study 1

BOTOX (N=64)

Placebo (N=62)

Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale†a -2.0* 0.0

Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††b -1.0* 0.0

Median Change from Baseline in Thumb Flexor Muscle Tone on the Ashworth Scale††c -1.0 -1.0

Median Physician Global Assessment of Response to Treatment†† 2.0* 0.0

†PrimaryendpointatWeek6††SecondaryendpointsatWeek6*Significantlydifferentfromplacebo(p≤0.05)aBOTOXinjectedintoboththeflexorcarpiradialisandulnarismusclesbBOTOXinjectedintotheflexordigitorumprofundusandflexordigitorumsublimismuscles

cBOTOXinjectedintotheadductorpollicisandflexorpollicislongusmusclesStudy2compared3dosesofBOTOXwithplaceboandincluded91patients[BOTOX360Units(N=21),BOTOX180Units(N=23),BOTOX90Units(N=21),andplacebo(N=26)]withupperlimbspasticity(expandedAshworthscoreofatleast2forelbowflexortoneandatleast3forwristflexortone)whowereatleast6weekspost-stroke.BOTOXandplacebowereinjectedwithEMGguidanceintotheflexordigitorumprofundus,flexordigitorumsublimis,flexorcarpiradialis,flexorcarpiulnaris,andbicepsbrachii(seeTable16).

Table 16: Study Medication Dose and Injection Sites in Study 2 and Study 3

Total Dose

Muscles Injected

BOTOX low

dose (90 Units)

BOTOX mid dose

(180 Units)

BOTOX high dose

(360 Units)

Volume (mL)

per site

Injection Sites (n)

Wrist Flexor Carpi Ulnaris 10 Units 20 Units 40 Units 0.4 1

Flexor Carpi Radialis 15 Units 30 Units 60 Units 0.6 1

Finger Flexor Digitorum Profundus 7.5 Units 15 Units 30 Units 0.3 1

Flexor Digitorum Sublimis 7.5 Units 15 Units 30 Units 0.3 1

Elbow Biceps Brachii 50 Units 100 Units 200 Units 0.5 4

TheprimaryefficacyvariableinStudy2wasthewristflexortoneatWeek6asmeasuredbytheexpandedAshworthScale.TheexpandedAshworthScaleusesthesamescoringsystemastheAshworthScale,butallowsforhalf-pointincrements.

KeysecondaryendpointsinStudy2includedPhysicianGlobalAssessment,fingerflexorsmuscletone,andelbowflexorsmuscletoneatWeek6.Study2resultsontheprimaryendpointandthekeysecondaryendpointsatWeek6areshowninTable17.

Table 17: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at Week 6 in Study 2

BOTOX low dose (90 Units)

(N=21)

BOTOX mid dose

(180 Units) (N=23)

BOTOX high dose (360 Units)

(N=21)

Placebo (N=26)

Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale†b

-1.5* -1.0* -1.5* -1.0

Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††c

-0.5 -0.5 -1.0 -0.5

Median Change from Baseline in Elbow Flexor Muscle Tone on the Ashworth Scale††d

-0.5 -1.0* -0.5a -0.5

Median Physician Global Assessment of Response to Treatment

1.0* 1.0* 1.0* 0.0

†PrimaryendpointatWeek6††SecondaryendpointsatWeek6*Significantlydifferentfromplacebo(p≤0.05)ap=0.053bTotaldoseofBOTOXinjectedintoboththeflexorcarpiradialisandulnarismuscles

cTotaldoseofBOTOXinjectedintotheflexordigitorumprofundusandflexordigitorumsublimismuscles

dDoseofBOTOXinjectedintobicepsbrachiimuscleStudy3compared3dosesofBOTOXwithplaceboandenrolled88patients[BOTOX360Units(N=23),BOTOX180Units(N=23),BOTOX90Units(N=23),andplacebo(N=19)]withupperlimbspasticity(expandedAshworthscoreofatleast2forelbowflexortoneandatleast3forwristflexortoneand/orfingerflexortone)whowereatleast6weekspost-stroke.BOTOXandplacebowereinjectedwithEMGguidanceintotheflexordigitorumprofundus,flexordigitorumsublimis,flexorcarpiradialis,flexorcarpiulnaris,andbicepsbrachii(seeTable16).

TheprimaryefficacyvariableinStudy3waswristandelbowflexortoneasmeasuredbytheexpandedAshworthscore.Akeysecondaryendpointwasassessmentoffingerflexorsmuscletone.Study3resultsontheprimaryendpointatWeek4areshowninTable18.

Table 18: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at Week 4 in Study 3

BOTOX low dose (90 Units)

(N=23)

BOTOX mid dose

(180 Units) (N=21)

BOTOX high dose (360 Units)

(N=22)

Placebo (N=19)

Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale†b

-1.0 -1.0 -1.5* -0.5

Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††c

-1.0 -1.0 -1.0* -0.5

Median Change from Baseline in Elbow Flexor Muscle Tone on the Ashworth Scale†d

-0.5 -0.5 -1.0* -0.5

†PrimaryendpointatWeek4††SecondaryendpointsatWeek4*Significantlydifferentfromplacebo(p≤0.05)bTotaldoseofBOTOXinjectedintoboththeflexorcarpiradialisandulnarismuscles

cTotaldoseofBOTOXinjectedintotheflexordigitorumprofundusandflexordigitorumsublimismuscles

dDoseofBOTOXinjectedintobicepsbrachiimuscle

14.4 Cervical DystoniaArandomized,multi-center,double-blind,placebo-controlledstudyofthetreatmentofcervicaldystoniawasconducted.ThisstudyenrolledadultpatientswithcervicaldystoniaandahistoryofhavingreceivedBOTOXinanopenlabelmannerwithperceivedgoodresponseandtolerablesideeffects.Patientswereexcludediftheyhadpreviouslyreceivedsurgicalorotherdenervationtreatmentfortheirsymptomsorhadaknownhistoryofneuromusculardisorder.SubjectsparticipatedinanopenlabelenrichmentperiodwheretheyreceivedtheirpreviouslyemployeddoseofBOTOX.Onlypatientswhowereagainperceivedasshowingaresponsewereadvancedtotherandomizedevaluationperiod.Themusclesinwhichtheblindedstudyagentinjectionsweretobeadministeredweredeterminedonanindividualpatientbasis.

Therewere214subjectsevaluatedfortheopenlabelperiod,ofwhich170progressedintotherandomized,blindedtreatmentperiod(88intheBOTOXgroup,82intheplacebogroup).Patientevaluationscontinuedforatleast10weekspost-injection.Theprimaryoutcomeforthestudywasadualendpoint,requiringevidenceofbothachangeintheCervicalDystoniaSeverityScale(CDSS)andanincreaseinthepercentageofpatientsshowinganyimprovementonthePhysicianGlobalAssessmentScaleat6weeksaftertheinjectionsession.TheCDSSquantifiestheseverityofabnormalheadpositioningandwasnewlydevisedforthisstudy.CDSSallots1pointforeach5degrees(orpartthereof)ofheaddeviationineachofthethreeplanesofheadmovement(rangeofscoresuptotheoreticalmaximumof54).ThePhysicianGlobalAssessmentScaleisa9categoryscalescoringthephysician’sevaluationofthepatients’statuscomparedtobaseline,rangingfrom–4to+4(verymarkedworseningtocompleteimprovement),with0indicatingnochangefrombaselineand+1slightimprovement.Painisalsoanimportantsymptomofcervicaldystoniaandwasevaluatedbyseparateassessmentsofpainfrequencyandseverityonscalesof0(nopain)to4(constantinfrequencyorextremelysevereinintensity).Studyresultsontheprimaryendpointsandthepain-relatedsecondaryendpointsareshowninTable19.

Table 19: Efficacy Outcomes of the Phase 3 Cervical Dystonia Study (Group Means)

Placebo (N=82)

BOTOX (N=88)

95% CI on Difference

Baseline CDSS 9.3 9.2

Change in CDSS at Week 6 -0.3 -1.3 (-2.3, 0.3)[a,b]

% Patients with Any Improvement on Physician Global Assessment 31% 51% (5%, 34%)[a]

Pain Intensity Baseline 1.8 1.8

Change in Pain Intensity at Week 6 -0.1 -0.4 (-0.7, -0.2)[c]

Pain Frequency Baseline 1.9 1.8

Change in Pain Frequency at Week 6 -0.0 -0.3 (-0.5, -0.0)[c]

[a]Confidenceintervalsareconstructedfromtheanalysisofcovariancetablewithtreatmentandinvestigationalsiteasmaineffects,andbaselineCDSSasacovariate.

[b]Thesevaluesrepresenttheprospectivelyplannedmethodformissingdataimputationandstatisticaltest.Sensitivityanalysesindicatedthatthe95%confidenceintervalexcludedthevalueofnodifferencebetweengroupsandthep-valuewaslessthan0.05.Theseanalysesincludedseveralalternativemissingdataimputationmethodsandnon-parametricstatisticaltests.

[c]Confidenceintervalsarebasedonthet-distribution.

Exploratoryanalysesofthisstudysuggestedthatthemajorityofpatientswhohadshownabeneficialresponsebyweek6hadreturnedtotheirbaselinestatusby3monthsaftertreatment.Exploratoryanalysesofsubsetsbypatientsexandagesuggestthatbothsexesreceivebenefit,althoughfemalepatientsmayreceivesomewhatgreateramountsthanmalepatients.Thereisaconsistenttreatment-associatedeffectbetweensubsetsgreaterthanandlessthanage65.Thereweretoofewnon-Caucasianpatientsenrolledtodrawanyconclusionsregardingrelativeefficacyinracialsubsets.

InthisstudythemediantotalBOTOXdoseinpatientsrandomizedtoreceiveBOTOX(N=88)was236Units,with25thto75thpercentilerangesof198Unitsto300Units.Ofthese88patients,mostreceivedinjectionsto3or4muscles;38receivedinjectionsto3muscles,28to4muscles,5to5muscles,and5to2muscles.ThedosewasdividedamongsttheaffectedmusclesinquantitiesshowninTable20.Thetotaldoseandmusclesselectedweretailoredtomeetindividualpatientneeds.

Table 20: Number of Patients Treated per Muscle and Fraction of Total Dose Injected into Involved Muscles

Muscle

Number of Patients Treated in this Muscle

(N=88)

Mean % Dose per Muscle

Mid-Range of % Dose per

Muscle*

Splenius capitis/cervicis 83 38 25-50

Sternocleidomastoid 77 25 17-31

Levator scapulae 52 20 16-25

Trapezius 49 29 18-33

Semispinalis 16 21 13-25

Scalene 15 15 6-21

Longissimus 8 29 17-41

*Themid-rangeofdoseiscalculatedasthe25thto75thpercentiles.

Therewereseveralrandomizedstudiesconductedpriortothedouble-blind,placebo-controlledstudy,whichweresupportivebutnotadequatelydesignedtoassessorquantitativelyestimatetheefficacyofBOTOX.

14.5 Primary Axillary HyperhidrosisTheefficacyandsafetyofBOTOXforthetreatmentofprimaryaxillaryhyperhidrosiswereevaluatedintworandomized,multi-center,double-blind,placebo-controlledstudies.Study1includedadultpatientswithpersistentprimaryaxillaryhyperhidrosiswhoscored3or4onaHyperhidrosisDiseaseSeverityScale(HDSS)andwhoproducedatleast50mgofsweatineachaxillaatrestover5minutes.HDSSisa4-pointscalewith1=“underarmsweatingisnevernoticeableandneverinterfereswithmydailyactivities”;to4=“underarmsweatingisintolerableandalwaysinterfereswithmydailyactivities”.Atotalof322patientswererandomizedina1:1:1ratiototreatmentinbothaxillaewitheither50UnitsofBOTOX,75UnitsofBOTOX,orplacebo.Patientswereevaluatedat4-weekintervals.Patientswhorespondedtothefirstinjectionwerere-injectedwhentheyreportedare-increaseinHDSSscoreto3or4andproducedatleast50mgsweatineachaxillabygravimetricmeasurement,butnosoonerthan8weeksaftertheinitialinjection.

Studyrespondersweredefinedaspatientswhoshowedatleasta2-gradeimprovementfrombaselinevalueontheHDSS4weeksafterbothofthefirsttwotreatmentsessionsorhadasustainedresponseaftertheirfirsttreatmentsessionanddidnotreceivere-treatmentduringthestudy.Spontaneousrestingaxillarysweatproductionwasassessedbyweighingafilterpaperheldintheaxillaoveraperiodof5minutes(gravimetricmeasurement).Sweatproductionresponderswerethosepatientswhodemonstratedareductioninaxillarysweatingfrombaselineofatleast50%atweek4.

InthethreestudygroupsthepercentageofpatientswithbaselineHDSSscoreof3rangedfrom50%to54%andfrom46%to50%forascoreof4.Themedianamountofsweatproduction(averagedforeachaxilla)was102mg,123mg,and114mgfortheplacebo,50Unitsand75Unitsgroupsrespectively.

Thepercentageofrespondersbasedonatleasta2-gradedecreasefrombaselineinHDSSorbasedona>50%decreasefrombaselineinaxillarysweatproductionwasgreaterinbothBOTOXgroupsthanintheplacebogroup(p<0.001),butwasnotsignificantlydifferentbetweenthetwoBOTOXdoses(seeTable21).

Durationofresponsewascalculatedasthenumberofdaysbetweeninjectionandthedateofthefirstvisitatwhichpatientsreturnedto3or4ontheHDSSscale.ThemediandurationofresponsefollowingthefirsttreatmentinBOTOXtreatedpatientswitheitherdosewas201days.AmongthosewhoreceivedasecondBOTOXinjection,themediandurationofresponsewassimilartothatobservedafterthefirsttreatment.

Instudy2,320adultswithbilateralaxillaryprimaryhyperhidrosiswererandomizedtoreceiveeither50UnitsofBOTOX(n=242)orplacebo(n=78).Treatmentrespondersweredefinedassubjectsshowingatleasta50%reductionfrombaselineinaxillarysweatingmeasuredbygravimetricmeasurementat4weeks.Atweek4post-injection,thepercentagesofresponderswere91%(219/242)intheBOTOXgroupand36%(28/78)intheplacebogroup,p<0.001.ThedifferenceinpercentageofrespondersbetweenBOTOXandplacebowas55%(95%CI=43.3,65.9).

Table 21: Study 1 - Study Outcomes

Treatment Response

BOTOX 50 Units (N=104)

BOTOX 75 Units (N=110)

Placebo (N=108)

BOTOX 50-placebo

(95% CI)

BOTOX 75-placebo

(95% CI)

HDSS Score change ≥2 (n)a

55% (57) 49% (54)

6% (6) 49.3% (38.8, 59.7)

43% (33.2, 53.8)

>50% decrease in axillary sweat production % (n)

81% (84) 86% (94)

41% (44) 40% (28.1, 52.0)

45% (33.3, 56.1)

aPatientswhoshowedatleasta2-gradeimprovementfrombaselinevalueontheHDSS4weeksafterbothofthefirsttwotreatmentsessionsorhadasustainedresponseaftertheirfirsttreatmentsessionanddidnotreceivere-treatmentduringthestudy.

14.6 BlepharospasmBotulinumtoxinhasbeeninvestigatedforuseinpatientswithblepharospasminseveralstudies.Inanopenlabel,historicallycontrolledstudy,27patientswithessentialblepharospasmwereinjectedwith2UnitsofBOTOXateachofsixsitesoneachside.Twenty-fiveofthe27patientstreatedwithbotulinumtoxinreportedimprovementwithin48hours.Onepatientwascontrolledwithahigherdosageat13weekspostinitialinjectionandonepatientreportedmildimprovementbutremainedfunctionallyimpaired.

Inanotherstudy,12patientswithblepharospasmwereevaluatedinadouble-blind,placebo-controlledstudy.Patientsreceivingbotulinumtoxin(n=8)improvedcomparedwiththeplacebogroup(n=4).Theeffectsofthetreatmentlastedameanof12weeks.

Onethousandsixhundredeighty-fourpatientswithblepharospasmwhowereevaluatedinanopenlabeltrialshowedclinicalimprovementasevaluatedbymeasuredeyelidforceandclinicallyobservedintensityoflidspasm,lastinganaverageof12weekspriortotheneedforre-treatment.

14.7 StrabismusSixhundredseventy-sevenpatientswithstrabismustreatedwithoneormoreinjectionsofBOTOXwereevaluatedinanopenlabeltrial.Fifty-fivepercentofthesepatientsimprovedtoanalignmentof10prismdioptersorlesswhenevaluatedsixmonthsormorefollowinginjection.

16 HOW SUPPLIED/STORAGE AND HANDLINGBOTOXissuppliedinasingle-usevialinthefollowingsizes:100UnitsNDC0023-1145-01200UnitsNDC0023-3921-02

VialsofBOTOXhaveaholographicfilmontheviallabelthatcontainsthename“Allergan”withinhorizontallinesofrainbowcolor.Inordertoseethehologram,rotatethevialbackandforthbetweenyourfingersunderadesklamporfluorescentlightsource.(Note:theholographicfilmonthelabelisabsentinthedate/lotarea.)Ifyoudonotseethelinesofrainbowcolororthename“Allergan”,donotusetheproductandcontactAllerganforadditionalinformationat1-800-890-4345from7:00AMto3:00PMPacificTime.

StorageUnopenedvialsofBOTOXshouldbestoredinarefrigerator(2°to8°C)forupto36monthsforthe100Unitsvialorupto24monthsforthe200Unitsvial.Donotuseaftertheexpirationdateonthevial.AdministerBOTOXwithin24hoursofreconstitution;duringthisperiodreconstitutedBOTOXshouldbestoredinarefrigerator(2°to8°C).ReconstitutedBOTOXshouldbeclear,colorless,andfreeofparticulatematter.

17 PATIENT COUNSELING INFORMATION“See FDA-approved patient labeling (Medication Guide)”ProvideacopyoftheMedicationGuideandreviewthecontentswiththepatient.

17.1 Swallowing, Speaking or Breathing Difficulties, or Other Unusual Symptoms

Patientsshouldbeadvisedtoinformtheirdoctororpharmacistiftheydevelopanyunusualsymptoms(includingdifficultywithswallowing,speaking,orbreathing),orifanyexistingsymptomworsens[see Boxed Warning and Warnings and Precautions (5.2, 5.5)].

17.2 Ability to Operate Machinery or VehiclesPatientsshouldbecounseledthatiflossofstrength,muscleweakness,blurredvision,ordroopingeyelidsoccur,theyshouldavoiddrivingacarorengaginginotherpotentiallyhazardousactivities.

17.3 Voiding Difficulties after Bladder InjectionsAfterbladderinjectionsforurinaryincontinence,patientsshouldbeinstructedtocontacttheirphysicianiftheyexperiencedifficultiesinvoiding.

Manufacturedby:AllerganPharmaceuticalsIrelandasubsidiaryof:Allergan,Inc.2525DupontDr.Irvine,CA92612

©2012Allergan,Inc.®markownedbyAllergan,Inc.U.S.Patents5,437,291;5,714,468;6,667,041;6,683,049;6,896,886;6,974,578;7,001,602;7,429,387;and7,449,192

Basedon72309US11Cand72312US11C

MEDICATION GUIDEBOTOX®

BOTOX® Cosmetic (Boe-tox)

(onabotulinumtoxinA) for Injection

ReadtheMedicationGuidethatcomeswithBOTOXorBOTOXCosmeticbeforeyoustartusingitandeachtimeitisgiventoyou.Theremaybenewinformation.Thisinformationdoesnottaketheplaceoftalkingwithyourdoctoraboutyourmedicalconditionoryourtreatment.Youshouldsharethisinformationwithyourfamilymembersandcaregivers.

What is the most important information I should know about BOTOX and BOTOX Cosmetic?

BOTOX and BOTOX Cosmetic may cause serious side effects that can be life threatening, including:

• Problems breathing or swallowing

• Spread of toxin effects

These problems can happen hours, days, to weeks after an injection of BOTOX or BOTOX Cosmetic. Call your doctor or get medical help right away if you have any of these problems after treatment with BOTOX or BOTOX Cosmetic:

1. Problems swallowing, speaking, or breathing. These problems can happen hours, days, to weeks after an injection of BOTOX or BOTOX Cosmetic usuallybecausethemusclesthatyouusetobreatheandswallowcanbecomeweakaftertheinjection.DeathcanhappenasacomplicationifyouhavesevereproblemswithswallowingorbreathingaftertreatmentwithBOTOX or BOTOX Cosmetic.

•Peoplewithcertainbreathingproblemsmayneedtousemusclesintheirnecktohelpthembreathe.ThesepeoplemaybeatgreaterriskforseriousbreathingproblemswithBOTOXorBOTOX Cosmetic.

•Swallowingproblemsmaylastforseveralmonths.Peoplewhocannotswallowwellmayneedafeedingtubetoreceivefoodandwater.Ifswallowingproblemsaresevere,foodorliquidsmaygointoyourlungs.PeoplewhoalreadyhaveswallowingorbreathingproblemsbeforereceivingBOTOXorBOTOX Cosmetichavethehighestriskofgettingtheseproblems.

2.Spread of toxin effects.Insomecases,theeffectofbotulinumtoxinmayaffectareasofthebodyawayfromtheinjectionsiteandcausesymptomsofaseriousconditioncalledbotulism.Thesymptomsofbotulisminclude:

•lossofstrengthandmuscleweaknessalloverthebody

•doublevision

•blurredvisionanddroopingeyelids

•hoarsenessorchangeorlossofvoice(dysphonia)

•troublesayingwordsclearly(dysarthria)

•lossofbladdercontrol

•troublebreathing

•troubleswallowing

Thesesymptomscanhappenhours,days,toweeksafteryoureceiveaninjectionofBOTOXorBOTOXCosmetic.

Theseproblemscouldmakeitunsafeforyoutodriveacarordootherdangerousactivities.See“WhatshouldIavoidwhilereceivingBOTOXorBOTOXCosmetic?”

TherehasnotbeenaconfirmedseriouscaseofspreadoftoxineffectawayfromtheinjectionsitewhenBOTOXhasbeenusedattherecommendeddosetotreatchronicmigraine,severeunderarmsweating,blepharospasm,orstrabismus,orwhenBOTOXCosmetichasbeenusedattherecommendeddosetotreatfrownlines.

What are BOTOX and BOTOX Cosmetic?

BOTOXisaprescriptionmedicinethatisinjectedintomusclesandused:

• totreatleakageofurine(incontinence)inadultswithoveractivebladderduetoneurologicdisease.

• topreventheadachesinadultswithchronicmigrainewhohave15ormoredayseachmonthwithheadachelasting4ormorehourseachday.

• totreatincreasedmusclestiffnessinelbow,wrist,andfingermusclesinadultswithupperlimbspasticity.

• totreattheabnormalheadpositionandneckpainthathappenswithcervicaldystonia(CD)inadults.

• totreatcertaintypesofeyemuscleproblems(strabismus)orabnormalspasmoftheeyelids(blepharospasm)inpeople12yearsandolder.

BOTOXisalsoinjectedintotheskintotreatthesymptomsofsevereunderarmsweating(severeprimaryaxillaryhyperhidrosis)whenmedicinesusedontheskin(topical)donotworkwellenough.

BOTOXCosmeticisaprescriptionmedicinethatisinjectedintomusclesandusedtoimprovethelookofmoderatetoseverefrownlinesbetweentheeyebrows(glabellarlines)inadultsyoungerthan65yearsofageforashortperiodoftime(temporary).

ItisnotknownwhetherBOTOXissafeoreffectiveinpeopleyoungerthan:

• 18yearsofagefortreatmentofurinaryincontinence

• 18yearsofagefortreatmentofchronicmigraine

• 18yearsofagefortreatmentofspasticity

• 16yearsofagefortreatmentofcervicaldystonia

• 18yearsofagefortreatmentofhyperhidrosis

• 12yearsofagefortreatmentofstrabismusorblepharospasm

BOTOXCosmeticisnotrecommendedforuseinchildrenyoungerthan18yearsofage.

ItisnotknownwhetherBOTOXandBOTOX Cosmeticaresafeoreffectivetopreventheadachesinpeoplewithmigrainewhohave14orfewerheadachedayseachmonth(episodicmigraine).

ItisnotknownwhetherBOTOXandBOTOXCosmeticaresafeoreffectiveforothertypesofmusclespasmsorforseveresweatinganywhereotherthanyourarmpits.

Who should not take BOTOX or BOTOX Cosmetic?

DonottakeBOTOXorBOTOXCosmeticifyou:• areallergictoanyoftheingredientsinBOTOXor

BOTOXCosmetic.SeetheendofthisMedicationGuideforalistofingredientsinBOTOXandBOTOXCosmetic.

• hadanallergicreactiontoanyotherbotulinumtoxinproductsuchasMyobloc®,Dysport®,orXeomin®

• haveaskininfectionattheplannedinjectionsite

• arebeingtreatedforurinaryincontinenceandhaveaurinarytractinfection(UTI)

• arebeingtreatedforurinaryincontinenceandfindthatyoucannotemptyyourbladderonyourown(onlyappliestopeoplewhoarenotroutinelycatheterizing)

What should I tell my doctor before taking BOTOX or BOTOX Cosmetic?

Tell your doctor about all your medical conditions, including if you:

• haveadiseasethataffectsyourmusclesandnerves(suchasamyotrophiclateralsclerosis[ALSorLouGehrig’sdisease],myastheniagravisorLambert-Eatonsyndrome).See“WhatisthemostimportantinformationIshouldknowaboutBOTOXandBOTOXCosmetic?”

• haveallergiestoanybotulinumtoxinproduct

• hadanysideeffectfromanybotulinumtoxinproductinthepast

• haveorhavehadabreathingproblem,suchasasthmaoremphysema

• haveorhavehadswallowingproblems

• haveorhavehadbleedingproblems

• haveplanstohavesurgery

• hadsurgeryonyourface

• haveweaknessofyourforeheadmuscles,suchastroubleraisingyoureyebrows

• havedroopingeyelids

• haveanyotherchangeinthewayyourfacenormallylooks

• havesymptomsofaurinarytractinfection(UTI)andarebeingtreatedforurinaryincontinence.Symptomsofaurinarytractinfectionmayincludepainorburningwithurination,frequenturination,orfever.

• haveproblemsemptyingyourbladderonyourownandarebeingtreatedforurinaryincontinence

• arepregnantorplantobecomepregnant.ItisnotknownifBOTOXorBOTOXCosmeticcanharmyourunbornbaby.

• arebreast-feedingorplantobreastfeed.ItisnotknownifBOTOXorBOTOXCosmeticpassesintobreastmilk.

Tell your doctor about all the medicines you take,includingprescriptionandnonprescriptionmedicines,vitaminsandherbalproducts.UsingBOTOXorBOTOXCosmeticwithcertainothermedicinesmaycauseserioussideeffects.Do not start any new medicines until you have told your doctor that you have received BOTOX or BOTOX Cosmetic in the past.

Especiallytellyourdoctorifyou:

• havereceivedanyotherbotulinumtoxinproductinthelastfourmonths

• havereceivedinjectionsofbotulinumtoxin,suchasMyobloc®(rimabotulinumtoxinB),Dysport®(abobotulinumtoxinA),orXeomin®(incobotulinumtoxinA)inthepast.Besureyourdoctorknowsexactlywhichproductyoureceived.

• haverecentlyreceivedanantibioticbyinjection

• takemusclerelaxants

• takeanallergyorcoldmedicine

• takeasleepmedicine

• takeanti-platelets(aspirin-likeproducts)and/oranti-coagulants(bloodthinners)

Ask your doctor if you are not sure if your medicine is one that is listed above.

Knowthemedicinesyoutake.Keepalistofyourmedicineswithyoutoshowyourdoctorandpharmacisteachtimeyougetanewmedicine.

How should I take BOTOX or BOTOX Cosmetic?

• BOTOXorBOTOXCosmeticisaninjectionthatyourdoctorwillgiveyou.

• BOTOXisinjectedintoyouraffectedmuscles,skin,orbladder.

• BOTOXCosmeticisinjectedintoyouraffectedmuscles.

• YourdoctormaychangeyourdoseofBOTOXorBOTOXCosmetic,untilyouandyourdoctorfindthebestdoseforyou.

• Your doctor will tell you how often you will receive your dose of BOTOX or BOTOX Cosmetic injections.

What should I avoid while taking BOTOX or BOTOX Cosmetic?

BOTOXandBOTOXCosmeticmaycauselossofstrengthorgeneralmuscleweakness,orvisionproblemswithinhourstoweeksoftakingBOTOXorBOTOXCosmetic.If this happens, do not drive a car, operate machinery, or do other dangerous activities. See“WhatisthemostimportantinformationIshouldknowaboutBOTOXandBOTOXCosmetic?”

What are the possible side effects of BOTOX and BOTOX Cosmetic?

BOTOX and BOTOXCosmetic can cause serious side effects. See“WhatisthemostimportantinformationIshouldknowaboutBOTOXandBOTOXCosmetic?”

Other side effects of BOTOX and BOTOX Cosmetic include:

• drymouth

• discomfortorpainattheinjectionsite

• tiredness

• headache

• neckpain

• eyeproblems:doublevision,blurredvision,decreasedeyesight,droopingeyelids,swellingofyoureyelids,anddryeyes.

• urinarytractinfectioninpeoplebeingtreatedforurinaryincontinence

• inabilitytoemptyyourbladderonyourownandarebeingtreatedforurinaryincontinence.

• allergicreactions.SymptomsofanallergicreactiontoBOTOXorBOTOXCosmeticmayinclude:itching,rash,reditchywelts,wheezing,asthmasymptoms,ordizzinessorfeelingfaint.Tellyourdoctororgetmedicalhelprightawayifyouarewheezingorhaveasthmasymptoms,orifyoubecomedizzyorfaint.

Tellyourdoctorifyouhaveanysideeffectthatbothersyouorthatdoesnotgoaway.

ThesearenotallthepossiblesideeffectsofBOTOXandBOTOXCosmetic.Formoreinformation,askyourdoctororpharmacist.

Callyourdoctorformedicaladviceaboutsideeffects.YoumayreportsideeffectstoFDAat1-800-FDA-1088.

General information about BOTOX and BOTOX Cosmetic:

MedicinesaresometimesprescribedforpurposesotherthanthoselistedinaMedicationGuide.

ThisMedicationGuidesummarizesthemostimportantinformationaboutBOTOXandBOTOXCosmetic.Ifyouwouldlikemoreinformation,talkwithyourdoctor.YoucanaskyourdoctororpharmacistforinformationaboutBOTOXandBOTOXCosmeticthatiswrittenforhealthcareprofessionals.FormoreinformationaboutBOTOXandBOTOXCosmeticcallAllerganat1-800-433-8871orgotowww.BOTOX.com.

What are the ingredients in BOTOX and BOTOX Cosmetic?

Activeingredient:botulinumtoxintypeAInactiveingredients:humanalbuminandsodiumchloride

Issued: 08/2011

ThisMedicationGuidehasbeenapprovedbytheU.S.FoodandDrugAdministration.

Manufacturedby:AllerganPharmaceuticalsIrelandasubsidiaryof:Allergan,Inc.2525DupontDr.Irvine,CA92612

©2012Allergan,Inc.®markownedbyAllergan,Inc.U.S.Patents5,437,291;5,714,468;6,667,041;6,683,049;6,896,886;6,974,578;7,001,602;7,429,387;and7,449,192

Myobloc®isaregisteredtrademarkofSolsticeNeurosciences,Inc.Dysport®isaregisteredtrademarkofIpsenBiopharmLimitedCompany.Xeomin®isaregisteredtrademarkofMerzPharmaGmbH&CoKGaA.

Basedon72309US11Cand72312US11C72284US13C

APC40NF12