A Treatment Option in the Management of

Chronic Migraine Patients

A supplement to oCtober 2012

this supplement is supported by Allergan, Inc. the content was edited by Allergan, Inc.

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S1

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S1

IndIcaTIOnchronic MigrainebotoX® (onabotulinumtoxinA) for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).

Important Limitationssafety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in 7 placebo-controlled studies.

Copyright © 2012 Quadrant HealthCom Inc. and Allergan, Inc.

COnTenTs

■ s3 Introduction ■ s4 Chronic migraine

Diagnosis and Classification ■ s7 botoX® (onabotulinumtoxinA)

efficacy and safety ■ s13 Injection paradigm and

Appropriate Candidates

EdITOrIaL Vice president/Group editor: Glenn s. Williams

PUBLISHInG publisher: elizabeth Katz

cUSTOM PrOGraMSVice president and Director: Carol nathanCustom programs manager: Amy saraiya

arT/PrOdUcTIOnArt Director: Jane FriedmanCreative Director: mary ellen niatasproduction manager: Jaime serra

cIrcULaTIOnCorporate Circulation Director: Donna sickles

nEW MEdIaDirector: Amy parkDigital program manager: Artie Krivopal

QUadranT HEaLTHcOM IncChairman: stephen stoneburnpresident and Chief executive officer: marcy Holetonpresident, Custom solutions: JoAnn WahlVice president, editorial Director: John baranowskiChief Financial officer: Douglas e. Grose

A Treatment Option in the Management of Chronic Migraine Patients

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 in-clude asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, uri-nary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks af-ter 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 about BOTOX® on the following pages. n october 2012 S2 S2 october 2012 n Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S3

Faculty

IMPOrTanT SaFETY InFOrMaTIOn (continued)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.

WarnInGS and PrEcaUTIOnS Lack of Interchangeability Between Botulinum Toxin Products The potency Units of BOTOX® are specific to the preparation and assay method utilized. They are not inter-changeable 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.

John rothrock, MdChief of neurosciencesuniversity of nevada, reno Director, neuroscience Instituterenown medical Centerreno, nV

Dr rothrock is Chief of the Division of neurosciences at the uni-versity of nevada school of medicine, and Director of the neu-rosciences Institute at the renown regional medical Center in reno. He also serves as editor-in-Chief of Headache, the journal of the American Headache society.

previously, Dr rothrock served as Chair of neurology and, subsequently, as Associate Dean for clinical research at the uni-versity of south Alabama before accepting a position as profes-sor (with tenure), Vice Chair and medical Director of neurology at the university of Alabama in 2006. prior to his time in Alabama, Dr rothrock established and directed the university of California, san Diego (uCsD) stroke Center and the uCsD Headache Center.

In 2007, he was cited in men’s Health magazine as one of the twenty top neurologists in America, and in 2008 he received the same citation in Women’s Health magazine. He was also cited in America’s top Doctors and best Doctors in America within each of the past ten years.

Dr rothrock received his medical degree from the university of Virginia and completed his internship and residency training in neurology at the university of Arizona.

andrew Blumenfeld, MdDirector, Headache Center of southern Californiasan Diego, CA

Dr blumenfeld is the Director of the Headache Center of south-ern California in san Diego. He is also the Co-Director of the sleep Center of southern California, as well as a partner of the research Center of southern California in oceanside. Dr blu-menfeld is board certified in neurology and Headache medicine.

Among his other positions, Dr blumenfeld is Chair of the American Headache society special section: peripheral nerve block & other Interventional procedures for Headache & Facial pain. He served as Chief of neurology service at Kaiser perma-nente, located in san Diego, California, and was Chairman of the bioethics committee.

In 2000, Dr blumenfeld received the Dystonia Doctor of ex-cellence Award and in 2003, the margaret treat excellence in ethics Award at Kaiser permanente.

Dr blumenfeld received a bachelor of medicine and surgery from the university of Witwatersrand, Johannesburg in south Africa. After moving to the united states in 1986, he completed a neurology residency and fellowship at the university of mas-sachusetts medical school.

dIScLOSUrESDr rothrock reports that he receives grant/research support from Allergan, Inc.; GlaxosmithKline; merck & Co., Inc.; and Zogenix, Inc. He is a consultant to Allergan, Inc.; mAp pharma-ceuticals, Inc.; and Zogenix, Inc. He is on the speakers’ bureau of GlaxosmithKline; merck & Co., Inc.; and Zogenix, Inc.

Dr blumenfeld reports that he receives grant/research support from Allergan, Inc.; Ipsen; merck & Co., Inc.; merz pharmaceu-ticals llC. He is a consultant to Allergan, Inc.; GlaxosmithKline; Keller laboratories; and Zogenix, Inc. He is on the speakers’ bureau of Allergan, Inc.; Forrest pharmaceuticals, Inc.; Glaxo-smithKline; mAp pharmaceuticals, Inc.; merck & Co., Inc.; and Zogenix, Inc.

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S2Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S3

Introduction

This supplement to neurology reviews is based on a video webcast that was recorded live in a new York City studio on Friday, march

23, 2012. In the webcast, we discuss botoX® (ona-botulinumtoxinA), the first and only treatment for prophylaxis of Chronic migraine in adult patients that is approved by the FDA.1

please note that botoX® is indicated for the pro-phylaxis of headaches in adult patients with Chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).1

Important limitationssafety and effectiveness have not been established for the prophylaxis of episodic migraine (14 head-ache days or fewer per month) in seven placebo-controlled studies.

Chronic migraine is a disabling condition that affects about 3.2 million Americans.2,3* Further-more, a survey showed that 80% (n=520) of Chronic migraine patients are undiagnosed.4

In this publication, we:• review efficacy and safety of botoX® in Chronic mi-

graine patients from preempt trials• Describe the approved injection paradigm for which

the results were demonstrated in the preempt

studies for the injection of botoX® in adults with Chronic migraine

• review some best practices for effective physi-cian patient dialogue to determine if a patient has Chronic migraine and is an appropriate candidate for botoX® (onabotulinumtoxinA)

• Discuss how best to set realistic expectations for botoX® treatment in appropriate patients with Chronic migraine.

this publication is an adaptation from a larg-er program that is a video webcast on the Identi-fication, Diagnosis, and management of Chronic migraine. When you have finished reading this pub-lication, we invite you to view the full presentations in the video webcast that is now available online at www.neurologyreviews.com in the multimedia library.

We thank Allergan, Inc, for supporting this pro-gram and the staff of neurology reviews and Quad-rant HealthCom for providing editorial support. Aller-gan provided editorial support as well. ■

John rothrock, mDAndrew blumenfeld, mD

*this number was determined by taking the publication’s Chronic migraine prevalence rate (1.4%) and applying it to 2010 us popula-tion estimates for those 18 or more years of age (n = 234,504,070).

IMPOrTanT SaFETY InFOrMaTIOn (continued)WarnInGS and PrEcaUTIOnS (continued)Spread of Toxin Effect see boxed Warning.

no definitive serious adverse event reports of distant spread of toxin effect associated with botoX® for chronic migraine at the labeled dose have been reported.

Injections In or near Vulnerable anatomic StructuresCare should be taken when injecting in or near vulnerable anatomic structures. serious adverse events including fatal outcomes have been reported in patients who had received botoX® injected directly into sali-vary glands, the oro-lingual-pharyngeal region, esophagus, and stomach. some patients had pre-existing dysphagia or significant debility. (safety and effectiveness have not been established for indications pertain-ing to these injection sites.) pneumothorax associated with injection procedure has been reported following the administration of botoX® near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices.

S4 october 2012 n

Chronic migraine is a defined condition. the International Headache society’s Interna-tional Classification of Headache Disorders,

2nd edition, revised (ICHD-2r) defines Chronic mi-graine as headache on 15 or more days per month for 3 or more months with 5 or more prior migraine attacks.5 the ICHD-2r definition also specifies that

on 8 or more days per month the headaches fulfill criteria for migraine, that the headaches are not attributed to another causative disorder, and that medication overuse is not a factor.

In clinical practice, however, many found this formal definition difficult to interpret, so in 2011 a simplified definition of Chronic migraine

was proposed (Figure 1).5,6

this new definition specifies that headaches occur on 15 or more days per month, the av-erage duration of headache is 4 or more hours per headache day, and that 8 or more days per month the headaches are linked to migraine. In this sim-plified definition Chronic mi-graine can exist with or with-out medication overuse.

A survey of 520 patients with Chronic migraine under the care of specialists showed that only 20% were accurate-ly diagnosed.4 this statistic reinforces the importance of effective patient communi-cation for accurate diagno-sis of Chronic migraine. tips to aid in communication and diagnosis:

Chronic Migraine Diagnosis and Classification

Figure 1: cHrOnIc MIGraInE: cUrrEnT STaTE OF cLaSSIFIcaTIOn and dIaGnOSIS5,6

Formal guidelines may be difficult to interpret:

proposed simplified classification:

Revised ICHD-2 Diagnostic Criteria for Chronic Migraine

(2006)5

Simplified Diagnosis for Chronic Migraine6

• Headache on ≥15 days/month ≥3 months with ≥5 prior migraine attacks

• On ≥8 days/month headache fulfills criteria for migraine

• Not attributed to another causative disorder

• Without medication overuse headache as defined in section 8.2 of the ICHD

• Headache more often than not (≥15 days/month)

and

• Average duration of ≥4 hours/day, ≥8 dayslinked to migraine

and

• With or without medication overuse

IMPOrTanT SaFETY InFOrMaTIOn (continued)WarnInGS and PrEcaUTIOnS (continued)Hypersensitivity reactions serious and/or immediate hypersensitivity reactions have been reported. these reactions include anaphy-laxis, 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 disorders Individuals 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®.

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S5

1. Have patients track headaches using diaries.2. Determine frequency using headache days vs

migraine attacks.3. Ask patients about their number of headache-

free days rather than days with headache.4. use open-ended questions to understand levels

of impairment.the American migraine Communication

study (n=60) showed that 55% of doctor-patient pairs were misaligned on their interpretation of headache frequency and that 51% of doctor-pa-tient pairs did not agree on the level of impair-ment.7 the authors therefore concluded that confirming migraine or headache frequency in days rather than attacks can lead to a more ac-curate diagnosis. In addition, the authors con-cluded that asking open-ended questions allows for better interpretation of headache-related impairment.8

“Best Practice” Encounter with a Patient during diagnosis of chronic MigraineIt is important to understand how to best man-age the dialogue with patients during diagnosis of Chronic migraine. be aware that patients may minimize the frequency of headache days by only focusing on the most severe migraine attacks. they may also have difficulty remembering all of their headache days. Ideally, the clinician starts the conversation by asking the initial 2 questions in the Ask-tell-Ask method.8 the patient’s answers indicate that the attacks are of long duration, but they do not allow the clinician to accurately deter-mine the frequency. At this point, the clinician asks about headache-free days in an effort to improve patient recall, and then returns to the Ask-tell-Ask method to confirm what was heard.

the clinician then looks to confirm a diagnosis of Chronic migraine by determining whether head-aches are linked to migraine on ≥8 days per month.7

to do so, the patient is asked to describe his or her headaches. the response confirms that most of the headaches are linked to migraine, thereby al-lowing the clinician to make a diagnosis of Chronic migraine.

Here is an example of a best-practice clini-cian-patient conversation:

clinician: How many migraine attacks are you getting each month?Patient: About 4 or 5.clinician: How long does each attack last?Patient: some last about half of the day, and others can last for several days.clinician: How many headache-free days did you have in the past month?Patient: I have about 10 days without headache each month.clinician: I see. You have about 10 days each month without headaches, which means that you have headaches on the other 20 days of the month. Is that correct?Patient: Yes. that’s about right.clinician: How would you describe your headaches?Patient: I generally get a severe throbbing pain on one or both sides of my head, and I sometimes feel nauseous. clinician: based on your responses, it appears you most likely have Chronic migraine.

“Best Practice” conversation about BOTOX® (onabotulinumtoxina) Prophylaxis With appropriate chronic Migraine Patients (≥15 headache days per month with headache lasting 4 hours a day or longer)Here is an example of a best-practice conversation with a patient after the clinician has suggested botoX® injection as an option.

IMPOrTanT SaFETY InFOrMaTIOn (continued)WarnInGS and PrEcaUTIOnS (continued)Human albumin and Transmission of Viral diseases this 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.

adVErSE rEacTIOnS the following adverse reactions to botoX® for injection are discussed in greater detail in the following sec-tions: spread of toxin effect (see boxed Warning); Hypersensitivity reactions (see Contraindications and Warnings and precautions).

S6 october 2012 n

clinician: From our discussion, and with your diagnosis of Chronic migraine, it sounds like botoX® (onabotulinumtoxinA) may be an option for you. Patient: Will it hurt? I’m worried about the injections and the side effects. clinician: botoX® injection is adminis-tered using a fine needle but there may still be some discomfort. neck pain is the most common side effect, and in the set-ting of a large clinical research study this occurred in 9% of patients treated with botoX® (compared to 3% with placebo). this does not cover all possible serious side effects of botoX® injection. I can review them with you in detail.Patient: Would botoX® injection replace my acute migraine therapy?clinician: no. botoX® injection is de-signed to help prevent headache days in patients with Chronic migraine, so it may increase the number of days each month that you don’t have a headache. You may still need to take your acute medication when you get a migraine.Patient: How quickly will I know if it is working? Is it going to work as quickly as my current medications?clinician: several weeks may be required to notice a response. In preempt 1 and 2, large-scale clinical studies investi-gating the safety and effectiveness of botoX® injection in Chronic migraine pa-tients, the first evaluation was at 4 weeks post injection and patients began to see some response at that evaluation point. patients experienced 2 treatment cycles to fully determine botoX® effectiveness

(as measured by the primary end point at 24 weeks) in preempt 1 and 2, so I would like to try at least 2 full injection cycles before we determine if it is working for you. I would also recommend that you keep a headache diary so you can track your progress and we accurately mea-sure your response to botoX® (onabotu-linumtoxinA) injection. this treatment is preventive, not abortive, so even if you are feeling well, it is recommended that it be repeated every 12 weeks until your doctor decides you no longer need it.

this sample dialogue illustrates several con-cerns patients may have regarding botoX®: pain associated with treatment, side effects, number of sets of injections needed, and when patients are expected to notice a response. the clinician responses acknowledge that patients may still feel some discomfort even though fine needles are used, and that neck pain occurred in 9% of patients treated with botoX® injection (compared with 3% with placebo).1 the clinician reminds the patient that this does not cover all possible se-rious side effects of botoX®, refers to the full prescribing Information including boxed Warning and medication Guide, and offers to discuss this further with the patient.

the clinician provides information that sev-eral weeks may be required to notice a response. In preempt 1 and 2, the first evaluation was at 4 weeks post injection. patients experienced 2 treatment cycles to determine botoX® effec-tiveness (as measured by the primary end point at 24 weeks) in preempt 1 and 2.9

the patient is also encouraged to keep a head-ache diary to monitor progress. ■

IMPOrTanT SaFETY InFOrMaTIOn (continued)adVErSE rEacTIOnS (continued)chronic Migraine the most frequently reported adverse reactions following injection of botoX® for chronic migraine include neck pain (9%), headache (5%), eyelid ptosis (4%), migraine (4%), muscular weakness (4%), musculoskel-etal stiffness (4%), bronchitis (3%), injection-site pain (3%), musculoskeletal pain (3%), myalgia (3%), facial paresis (2%), hypertension (2%), and muscle spasms (2%).

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S7

Primary Time Point

-4

Baseline

Wee

ks

BOTOX® vsPlacebo (saline)

BOTOX® vsPlacebo (saline)

BOTOX®

• Headache symptoms and medications were recorded in a daily telephone diary

• Large clinical program of Chronic Migraine sufferers (1384 patients)

BOTOX® BOTOX®

Phone Interview Treatment

Double-Blind Phase

BOTOX® vs Placebo

Open-Label Phase

All Patients on BOTOX®

Day0 5620161284 444036 5248322824

Randomization

1 2 3 4 5

Figure 1: STUdY dESIGn OF TWO PHaSE 3 STUdIES OF cHrOnIc MIGraInE PaTIEnTS9,10

BOTOX® (onabotulinumtoxinA) efficacy and safetyclinical Trialspreempt, or Phase 3 research Evaluating Migraine Prophylaxis Therapy, was a clinical study of Chronic migraine involving 1384 patients who av-eraged approximately 20 headache days per month at baseline (Figure 1).9,10 preempt comprised 2 parallel trials.

the preempt 1 and preempt 2 studies were multicenter, placebo-controlled, parallel-group, phase 3 clinical trials.9,11 In total, these studies were conducted at 122 sites in 6 different coun-tries, including 95 sites in the us, 11 sites in Cana-da, and 16 sites in europe. each trial consisted of a 28-day baseline phase, then a 24-week double-blind treatment phase during which patients received injections of botoX® (onabotulinum-toxinA) or placebo every 12 weeks (at day 0 and week 12). throughout the studies, patients

used a daily interactive telephone diary to re-cord their headache symptoms and medications.

the inclusion and exclusion criteria in the two preempt phase 3 trials were identical.9,11 both enrolled men or women, aged 18 to 65 years, who had a history of migraine as defined in section 1 of the International Classification of Headache Dis-orders, 2nd edition (ICHD-2), with the exception of “complicated migraine” (ie, hemiplegic migraine, basilar-type migraine, ophthalmoplegic migraine, or migrainous infarction).

During the 4-week baseline period, eligible patients were required to have headaches on 15 or more days, with each day consisting of at least 4 hours of continuous headache, and ≥50% of the baseline headache days being migraine or probable migraine days. In addition, as one of the end points in the study was reduction in headache

IMPOrTanT SaFETY InFOrMaTIOn (continued)adVErSE rEacTIOnS (continued)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 infarc-tion, 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.

S8 october 2012 n

episodes, patients were required to have at least 4 distinct headache episodes, each lasting for at least 4 hours.

patients were excluded if they had any medical condition that would put them at increased risk if they were exposed to botoX® (onabotulinumtoxinA),diagnosis of other primary or secondary headache disorders, use of any prophylactic headache medi-cation within 28 days before entering the baseline phase, beck Depression Inventory score >24, or previous exposure to any botulinum toxin serotype.

patients with overuse of acute headache medi-cations were not excluded; however, the random-ization was stratified for medication overuse to ensure that the botoX® and placebo groups were well balanced in terms of baseline characteristics.

the key baseline characteristics of pa-

tients that participated in preempt 1 and 2 re-flect those of a typical Chronic migraine patient (Table 1).11,12 mean age was 41 and most were female.5 mean headache days were approxi-mately 20 for both groups.11 Approximately 62% of botoX® (onabotulinumtoxinA) patients and 65% of placebo patients had received prior prophylactic therapy.5 Approximately 65% of botoX® patients and approximately 66% of placebo patients were overusing acute headache pain medications, de-fined as having taken acute headache pain medi-cation at least twice per week in any week with 5 or more diary days and greater than or equal to 10 to 15 days during the baseline period.12

results from the preempt trials show sig-nificant reductions from baseline in headache days through 24 weeks. In preempt 1, patients who

Table 1: cHaracTErISTIcS OF a TYPIcaL cHrOnIc MIGraInE PaTIEnT: KEY BaSELInE cHaracTErISTIcS FrOM PrEEMPT 1 and 2 11,12

BOTOX® (onabotulinumtoxina)

n=688

Placebo (n=696)

mean age11 41.1 years 41.5 years

Female, %11 88% 85%

mean headache days (sD)11 19.9 (3.7) 19.8 (3.7)

prior prophylactic therapy12 62% 65%

percent overusing acute headache pain medications*11

65% 66%

severe headache impact (HIt-6† score ≥60)11

94% 93%

*Patients must have taken acute headache pain medication at least twice per week in any week with ≥ 5 diary days and ≥10 to 15 days (depending on medication category) during the baseline period.†HIT-6=Headache Impact Test-6.

IMPOrTanT SaFETY InFOrMaTIOn (continued)drUG InTEracTIOnS no 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 potenti-ated. use of anticholinergic drugs after administration of botoX® may potentiate systemic anticholinergic effects. the effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.excessive weakness may also be exaggerated by administration of a muscle relaxant before or after admin-istration of botoX®.

Please see accompanying full Prescribing Information, including Boxed Warning and Medication Guide.

Please see Important Safety Information including Boxed Warning about BOTOX® on the following pages. n october 2012 S9

received botoX® (onabotulinumtoxinA) injections had 7.8 fewer headache days per month at week 24 compared with baseline, whereas those given pla-cebo had 6.4 fewer headache days—a difference that was statistically significant (p ≤0.05) (Figure 2a).1 A significant difference in headache days per month favoring botoX® over placebo was also evi-dent at weeks 4, 8, 12, and 20.13 In preempt 2, patients who received botoX® had 9.2 fewer headache days per month at week 24 com-pared with baseline versus 6.9 fewer headache days per month in the placebo group (p ≤0.05) (Figure 2b).1

therefore, the preempt trials show that patients taking botoX® had 8 to 9 fewer headache days per month compared with baseline, versus 6 to 7 days with placebo, at 24 weeks.1

All patients received botoX® during the open label phase.

As noted previously, in pre-empt 2, patients who received botoX® injection had 9.2 fewer headache days per month at week 24 compared with baseline versus 6.9 fewer headache days per month in the placebo group (p ≤0.05).1 pa-tients treated with botoX® had a significantly greater mean de-crease from baseline in the fre-quency of headache days at all timepoints from Week 4 to Week 24 in preempt 2 compared to placebo- treated patients.1

All patients received botoX® during the open-label phase.

A responder analysis was con-ducted to identify patients who had a ≥50% reduction from baseline in headache days each month at week

24 (Figure 3a).13,14 In preempt 1, 44% (n=341) of pa-tients who received botoX® (onabotulinumtoxinA)neurotoxin compared with 36% (n=338) of those given placebo achieved this level of response—

0

After week 24 all patients received BOTOX®

BOTOX® (n=341)Placebo (n=338)

a

a a

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Figure 2a: rESULTS FrOM PrEEMPT 11

Figure 2b: rESULTS FrOM PrEEMPT 21

* A headache day was defined as a calendar day per 28 days with ≥4 continuous hours of headache.

* A headache day was defined as a calendar day per 28 days with ≥4 continuous hours of headache.

IndIcaTIOnchronic MigrainebotoX® (onabotulinumtoxinA) for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).

Important Limitationssafety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in 7 placebo-controlled studies.

S10 october 2012 n

a difference that did not achieve statistical significance.13

In preempt 2, the difference between botoX® (onabotulinumtoxinA) versus placebo was signifi-cant with a p <.001. In this study, 51% (n=347) of patients who received botoX® had a ≥50% reduc-tion from baseline in headache days each month compared with 34% (n=358) of those in the placebo arm (Figure 3b).14

Table 2 summarizes the adverse reactions that were reported by ≥2% of patients treated with botoX® and that occurred more frequently than in patients receiving placebo in two Chronic migraine double-blind placebo-controlled clinical trials. neck pain and headache were reported at an incidence of

5% or higher.1 neck pain was reported in 9% of pa-tients treated with botoX® (onabotulinumtoxinA) compared to 3% of those given placebo, and head-ache was reported in 5% in patients receiving botoX® compared to 3% of those given placebo.

other adverse reactions that occurred more fre-quently in the botoX® treatment group than in the placebo group at a rate <1%, which were potentially related to botoX® included: vertigo, dry eye, eyelid edema, dysphagia, eye infection, and jaw pain.1

severe worsening of migraine requiring hospi-talization occurred in approximately 1% of patients treated with botoX® in preempt 1 and preempt 2,usually within the first week after treatment (com-pared to 0.3% of placebo-treated patients).1 ■

BOTOX® (n=341)

Placebo (n=338)

aP=NS

44%a

36%

100

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50

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Figure 3b: rESULTS FrOM PrEEMPT 214Figure 3a: rESULTS FrOM PrEEMPT 113,14

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, dysar-thria, 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 unap-proved 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.

Significant difference in BOTOX® vs placebo in PrEEMPT 2 but not PrEEMPT 1

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S11

adverse reactions by body system BOTOX® 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%)

Table 2: adVErSE rEacTIOnS rEPOrTEd BY ≥2% OF BOTOX® TrEaTEd PaTIEnTS and MOrE FrEQUEnTLY THan In PLacEBO-TrEaTEd PaTIEnTS In TWO cHrOnIc MIGraInE dOUBLE-BLInd PLacEBO-cOnTrOLLEd cLInIcaL TrIaLS1

IMPOrTanT SaFETY InFOrMaTIOn (continued)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.

WarnInGS and PrEcaUTIOnS Lack of Interchangeability Between Botulinum Toxin Products The 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.

S12 october 2012 n

The efficacy demonstrated in the preempt trials was established using the injection paradigm that was ultimately approved by

the FDA. botoX® (onabotulinumtoxinA) is admin-istered in a total dosage of 155 units divided into 31 fixed-site, fixed-dose intramuscular injections across 7 specific head/neck muscle areas (fronta-lis, corrugator, procerus, occipitalis, temporalis, trapezius, and cervical paraspinal muscle group).1

Dose and injection sites used in preempt were identified from an in-depth analysis of all phase 2 studies over a 10-year period by assessing interactions between muscle group and efficacy parameters, and between dose/dosing paradigm and safety parameters.15

dilution Instructions for Use of BOTOX® (onabotulinumtoxina)botoX® is supplied in single-use vials containing either 100 or 200 units.1 prior to use, the vacu-um-dried vial of botoX® should be reconstituted with sterile, preservative-free 0.9% sodium Chlo-ride Injection, usp. the proper amount of the sa-line diluent (2 ml for 100-unit vials or 4 ml for 200-unit vials) should be drawn into an appropri-ate sized syringe, and then slowly injected into the vial (Table 1).1 the vial should be discarded if a vacuum does not pull the diluent into the vial. the vial should be slowly rotated to reconstitute the botoX® in the diluent, and then the date and time should be recorded in the space on the vial label.

Table 1: dILUTIOn InSTrUcTIOnS FOr USE OF BOTOX® (onabotulinumtoxina)1

100 Unit Vial 200 Unit Vial

Volume of saline* to be added 2 ml 4 ml

resulting botoX® dose 5 units per 0.1 ml 5 units per 0.1 ml

*preservative-free 0.9% sodium Chloride Injection, usp only

once reconstituted, botoX® must be injected or immediately stored in the refrigerator (2ºC to 8ºC) and used within 24 hours.

Injection Paradigm and Appropriate Candidates

IMPOrTanT SaFETY InFOrMaTIOn (continued)WarnInGS and PrEcaUTIOnS (continued)Spread of Toxin Effect see boxed Warning.

no definitive serious adverse event reports of distant spread of toxin effect associated with botoX® for chronic migraine at the labeled dose have been reported.

Injections In or near Vulnerable anatomic StructuresCare should be taken when injecting in or near vulnerable anatomic structures. serious adverse events including fatal outcomes have been reported in patients who had received botoX® injected directly into salivary glands, the oro-lingual-pharyngeal region, esophagus, and stomach. some patients had pre-ex-isting dysphagia or significant debility. (safety and effectiveness have not been established for indications pertaining to these injection sites.) pneumothorax associated with injection procedure has been reported following the administration of botoX® near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S13

IMPOrTanT SaFETY InFOrMaTIOn (continued)WarnInGS and PrEcaUTIOnS (continued) Hypersensitivity reactions serious and/or immediate hypersensitivity reactions have been reported. these reactions include anaphy-laxis, 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 disorders Individuals 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®.

the reconstituted botoX® (onabotulinumtoxinA) should be clear, colorless, and free of particulate matter. botoX® injection should be administered within 24 hours after reconstitution. During this time period, the reconstituted botoX® should be stored in a refrigerator.

Injection Paradigmthe injection paradigm involves 31 injections to 7 specific head/neck muscle areas (Figure 1).1,6,15

each muscle should be palpated prior to in-jection in order to verify the muscle delin-eation. With patients in the supine position,

Figure 1: rEcOMMEndEd InJEcTIOn SITES FOr cHrOnIc MIGraInE PaTIEnTS1,6,15

SUPInE SITTInG

A. Corrugator5 u each side

b. procerus5 u (one side)

C. Frontalis10 u each side

D. temporalis20 u each side

e. occipitalis15 u each side

F. Cervical paraspinal 10 u each slide

G. trapezius15 u each side

recommended order of injection: a g G based on PrEEMPT paradigm3

BOTOX® (5 Units in 0.1 mL) injected IM at each site using sterile 30-gauge, 0.5 inch needle; a 1-inch needle may be used in neck regions for patients with thick neck muscles1

S14 october 2012 n

Table 2: BOTOX® (OnaBOTULInUMTOXIna) dOSInG BY MUScLE FOr cHrOnIc MIGraInE PaTIEnTS1

Order* Head/neck area recommended dose†

A Corrugator** 10 units divided in 2 sites

b procerus 5 units in 1 site

C Frontalis** 20 units divided in 4 sites

D temporalis** 40 units divided in 8 sites

e occipitalis** 30 units divided in 6 sites

F Cervical paraspinal** 20 units divided in 4 sites

G trapezius** 30 units divided in 6 sites

Total dose 155 Units divided in 31 sites

the dosing and administration of botoX® is a detailed process. the information in this table contains highlights only and is not meant to be a substitute for appropriate training or review of full prescribing Information.

*recommended order of injection based on preempt injection paradigm**Dose distributed bilaterally†each Im injection site receives 5 units botoX® in 0.1 ml

botoX® (onabotulinumtoxinA) should be adminis-tered into the corrugator, procerus, frontalis, and temporalis muscles, in that order. patients should then be moved to a sitting position, and then botoX® should be administered into the occipi-talis, cervical paraspinal, and trapezius muscles, in that order. For bilateral muscles, the injections should be made to the left side first at the specified sites, and then repeated on the right side before moving to the next muscle area. this allows a cli-nician to easily recall where he/she gave the last

injection and helps to avoid missed or duplicate injections.

each intramuscular injection should deliver 5 units of botoX® (onabotulinumtoxinA) in a vol-ume of 0.1 ml. A sterile 30-gauge, 0.5-inch needle should be used. A 1-inch needle may be used in neck regions for patients with thick muscles.1

standard sterile procedures for intramuscular injection should be used (eg, swabbing each in-jection site with alcohol).15 the needle should be inserted into the muscle with the bevel up, at ap-

IMPOrTanT SaFETY InFOrMaTIOn (continued)WarnInGS and PrEcaUTIOnS (continued) Human albumin and Transmission of Viral diseases this 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.

adVErSE rEacTIOnS the following adverse reactions to botoX® for injection are discussed in greater detail in the following sec-tions: spread of toxin effect (see boxed Warning); Hypersensitivity reactions (see Contraindications and Warnings and precautions).

Please see additional Important Safety Information about BOTOX® on the following pages. n october 2012 S15

proximately a 45-degree angle. After insertion, the hub of the needle should be held with one hand, and the plunger pulled back with the other hand to ensure no blood return. then, the injection may be administered. Gentle pressure is applied if bleed-ing or bruising occurs.

Table 2 reiterates the order of injection ac-cording to the preempt injection paradigm and shows the total dose delivered to each head/neck muscle area.1 each Im injection site receives 5 units botoX® (onabotulinumtoxinA) in 0.1 ml. For bilat-eral muscles, the dose represents the total dose de-livered to the left side and right side. For example, injections are made into 2 sites in the frontalis mus-cle on the left side followed by injections into 2 sites on the right side. therefore, the total dose delivered to the frontalis is 20 units divided in 4 sites. overall, the recommended dose of botoX® is 155 units de-livered as 31 fixed-dose, fixed-site injections across the 7 specific head/neck muscle areas.

the dosing and administration of botoX® is a detailed process. the information in Table 2 contains highlights only and is not meant to be a substitute for appropriate training or review of full prescribing Information.

Selecting appropriate candidates for BOTOX® TreatmentbotoX® is indicated for the prophylaxis of head-aches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).1

Important Limitations safety and effectiveness have not been estab-lished for the prophylaxis of episodic migraine (14 headache days or fewer per month) in 7 placebo- controlled studies.

open dialogue with the patient is important to reach an appropriate diagnosis.

Setting Patient Expectations for BOTOX® (onabotulinumtoxina) Treatment It is important to establish realistic expectations when discussing botoX® treatment for appropri-ate Chronic migraine patients. patients are used to having abortive migraine medications work quick-ly, and may get discouraged if they do not see im-mediate benefit from botoX®.

the rationale for Chronic migraine prophylaxis should be explained to patients, and it should be distinguished from their acute migraine medica-tions.16 specifically, prophylaxis is designed to re-duce the frequency of headache days.4,6 patients taking botoX® had 8 to 9 fewer headache days per month compared with baseline, versus 6 to 7 days with placebo, at 24 weeks.4,6

patients may have inappropriate expecta-tions with botoX® injections. Chronic migraine patients may be familiar with the rapid onset when using injectable medications for abortive treatment. patients may then erroneously expect immediate benefit from their botoX® treatment, which is preventive, not abortive. therefore, pa-tients should be told that several weeks may be required to notice a response.9,11 In preempt 1 and 2, the first evaluation was at 4 weeks post injection and at that point patients had begun to see some response. patients experienced 2 treat-ment cycles to fully determine botoX® effective-ness (as measured by the primary end point at 24 weeks) in preempt 1 and 2.

patients should be encouraged to maintain a headache diary in order to track their progress, because patient recall about headaches occurring weeks before may not always be accurate.

IMPOrTanT SaFETY InFOrMaTIOn (continued)adVErSE rEacTIOnS (continued) chronic Migraine the most frequently reported adverse reactions following injection of botoX® for chronic migraine include neck pain (9%), headache (5%), eyelid ptosis (4%), migraine (4%), muscular weakness (4%), musculoskel-etal stiffness (4%), bronchitis (3%), injection-site pain (3%), musculoskeletal pain (3%), myalgia (3%), facial paresis (2%), hypertension (2%), and muscle spasms (2%).

additional educational tools and resourc-es including injection videos can be found by visiting www.botoxchronicmigraine.com/hcp.

S16 october 2012 n

rEIMBUrSEMEnT InFOrMaTIOnbotoX® (onabotulinumtoxinA) has broad reim-bursement coverage for Chronic migraine, for both commercial and medicare plans. extensive reim-bursement support services for physicians and as-sistance programs for patients are available.

Comprehensive support for providers is available through botoX® reimbursement solutions:

• personalized reimbursement support is available online, via phone, or in person

• Visit botoXreimbursementsolutions.com or call 1-800-44-botoX, option 4

Access assistance for patients is also available:• botoX® partnership for Access prepaid mas-

terCard®* program helps eligible commercially insured patients with out-of-pocket treatment costs. the botoX® partnership for Access pre-paid masterCard® is valid at participating loca-tions and cannot be used at merchants outside the united states (including Internet and mail/telephone order merchants outside of the unit-ed states). this card is issued by metabank™ pursuant to license by masterCard® Interna-tional Incorporated.

• botoX pAtIent AssIstAnCe® program provides botoX® at no charge for eligible uninsured/un-derinsured patients.

SUMMarYbotoX® (onabotulinumtoxinA) is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with head-ache lasting 4 hours a day or longer).1

Important Limitations safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 head-ache days or fewer per month) in 7 placebo-con-trolled studies.

patients taking botoX® in the preempt trials had 8 to 9 fewer headache days per month (versus 6 to 7 days with placebo) at 24 weeks.11 botoX® is administered using a fixed-site, fixed dose injec-tion paradigm, with 155 units administered to 31 injection sites across 7 head/neck muscle areas.1

physician/patient dialogue is key at all stages from diagnosis to consideration of appropriate treatment options.9 When botoX® injection is cho-sen as a treatment option, the clinician provides information about the injection procedure, points out that several weeks may be required to notice a response, and encourages the patient to keep a headache diary to monitor progress.

extensive reimbursement support services for providers and assistance programs for patients are available. ■

* the botoX® partnership for Access prepaid masterCard is valid at participating locations and cannot be used at merchants outside the united states (including Internet and mail/telephone order merchants outside of the united states). this card is issued by metabanktm pursuant to license by masterCard® International Incorporated.

IMPOrTanT SaFETY InFOrMaTIOn (continued)adVErSE rEacTIOnS (continued) 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 infarc-tion, 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.

n october 2012 S17

IMPOrTanT SaFETY InFOrMaTIOn (continued)drUG InTEracTIOnS no 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 potenti-ated. use of anticholinergic drugs after administration of botoX® may potentiate systemic anticholinergic effects. the effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.excessive weakness may also be exaggerated by administration of a muscle relaxant before or after admin-istration of botoX®.

Please see accompanying full Prescribing Information, including Boxed Warning and Medication Guide.

Copyright© 2012 Quadrant HealthCom Inc. and Allergan, Inc.©2012 Allergan, Inc., Irvine, CA 92612

botoX® marks owned by Allergan, Inc.masterCard is a registered trademark of masterCard International Incorporated.

metabank is a trademark of metabank.www.botoXmedical.com/HCp

references 1. botoX® (onabotulinumtoxinA). prescribing information.

Allergan, Inc. november, 2011. 2. natoli Jl, manack A, Dean b, et al. Global prevalence

of chronic migraine: a systematic review. Cephalalgia. 2010;30:559-609.

3. Centers for Disease Control and prevention. population projections, united states, 2004-2030, on CDC WonDer on-line Database, september 2005. Available at: http://wonder.cdc.gov/population-projections.html. Accessed January 9, 2012.

4. bigal me, serrano D, reed m, lipton rb. Chronic migraine in the population. burden, diagnosis, and satisfaction with treatment. neurology. 2008;71:559-566.

5. Headache Classification Committee, olesen J, bouss-er mG, Diener HC, et al. new appendix criteria open for a broader concept of chronic migraine. Cephalalgia. 2006;26(6):742-746.

6. lipton rb. Chronic migraine, classification, differential di-agnosis, and epidemiology. Headache. 2011;51(s2):77-83.

7. lipton rb, Hahn sr, Cady rK, brandes Jl, simons se, bain pA, nelson mr. In-office discussions of migraine: re-sults from the American migraine Communication study. J Gen Intern med. 2008 Aug;23(8):1145-1151.

8. buse DC, lipton rb. Facilitating communication with pa-tients for improved migraine outcomes. Curr pain Head-

ache rep. 2008;12:230-236. 9. Aurora sK, Winner p, Freeman mC, et al. onabotulinum-

toxinA for treatment of chronic migraine: pooled analy-sis of the 56-week prempt clinical program. Headache. 2011;51:1358-1373.

10. Diener HC, Dodick DW, Aurora sK, et al. onabotulinum-toxinA for treatment of chronic migraine: results from the doubleblind, randomized, placebo-controlled phase of the prempt 2 trial. Cephalalgia. 2010;30(7):804-814.

11. Dodick DW, turkel CC, DeGryse re, et al. onabotulinum-toxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo controlled phases of the prempt clinical program. Headache. 2010;50:921-936.

12. Data on File, Allergan, Inc.; Integrated summary of effi-cacy.

13. Data on file, Allergan, Inc.; prempt 1 Final report.14. Data on file, Allergan, Inc.; prempt 2 Final report.15. blumenfeld A, silberstein sD, Dodick DW, Aurora sK,

turkel CC, binder WJ. method of injection of onabotu-linumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment paradigm based on the prempt clinical program. Headache. 2010 oct;50(9):1406-1418.

16. D’Amico D, tepper sJ. prophylaxis of migraine: general principles and patient acceptance. neuropsychiatr Dis treat. 2008;4:1155-1167.

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)].Thesepatientsshouldbeconsideredforfurthermedicalevaluationandappropriatemedicaltherapyimmediatelyinstituted,whichmayincludehospitalization.

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

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.

**PrimaryTimepointa Primaryendpointb Secondaryendpoint

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.

**PrimaryTimepointa Primaryendpointb Secondaryendpoint

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)a BOTOXinjectedintoboththeflexorcarpiradialisandulnarismusclesb BOTOXinjectedintotheflexordigitorumprofundusandflexordigitorumsublimismuscles

c BOTOXinjectedintotheadductorpollicisandflexorpollicislongusmuscles

Study2compared3dosesofBOTOXwithplaceboandincluded91patients[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)a p=0.053b TotaldoseofBOTOXinjectedintoboththeflexorcarpiradialisandulnarismuscles

c TotaldoseofBOTOXinjectedintotheflexordigitorumprofundusandflexordigitorumsublimismuscles

d DoseofBOTOXinjectedintobicepsbrachiimuscle

Study3compared3dosesofBOTOXwithplaceboandenrolled88patients[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)b TotaldoseofBOTOXinjectedintoboththeflexorcarpiradialisandulnarismuscles

c TotaldoseofBOTOXinjectedintotheflexordigitorumprofundusandflexordigitorumsublimismuscles

d DoseofBOTOXinjectedintobicepsbrachiimuscle

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.Patented.See:www.allergan.com/products/patent_notices

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.DeathcanhappenasacomplicationifyouhavesevereproblemswithswallowingorbreathingaftertreatmentwithBOTOXorBOTOXCosmetic.

•Peoplewithcertainbreathingproblemsmayneedtousemusclesintheirnecktohelpthembreathe.ThesepeoplemaybeatgreaterriskforseriousbreathingproblemswithBOTOXorBOTOXCosmetic.

•Swallowingproblemsmaylastforseveralmonths.Peoplewhocannotswallowwellmayneedafeedingtubetoreceivefoodandwater.Ifswallowingproblemsaresevere,foodorliquidsmaygointoyourlungs.PeoplewhoalreadyhaveswallowingorbreathingproblemsbeforereceivingBOTOXorBOTOXCosmetichavethehighestriskofgettingtheseproblems.

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.

ItisnotknownwhetherBOTOXandBOTOXCosmeticaresafeoreffectivetopreventheadachesinpeoplewithmigrainewhohave14orfewerheadachedayseachmonth(episodicmigraine).

ItisnotknownwhetherBOTOXandBOTOXCosmeticaresafeoreffectiveforothertypesofmusclespasmsorforseveresweatinganywhereotherthanyourarmpits.

Who should not take BOTOX or BOTOX Cosmetic?

DonottakeBOTOXorBOTOXCosmeticifyou:• areallergictoanyoftheingredientsinBOTOXorBOTOXCosmetic.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.Patented.See:www.allergan.com/products/patent_notices

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

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