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

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

                                                   BOTOX
                                                                                       ®

                                                   DELIVERS.

Indication
Detrusor Overactivity Associated With a Neurologic Condition
BOTOX® for injection is indicated for the treatment of urinary incontinence due to detrusor overactivity
associated with a neurologic condition (eg, spinal cord injury [SCI], multiple sclerosis [MS]) in adults who
have an inadequate response to or are intolerant of an anticholinergic medication.
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING

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

Please see additional Important Safety Information inside.
Please see accompanying full Prescribing Information,
including Boxed Warning.
BOTOX DELIVERS. For your adult patients with incontinence due to neurogenic detrusor overactivity (NDO) refractory to an anticholinergic
NDO and a Treatment

More than half of patients with the following neurologic conditions
may have detrusor overactivity (DO)1,2:
  • Multiple sclerosis (MS)      • Parkinson’s disease (PD)
  • Spinal cord injury (SCI)     • Stroke

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

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

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

• In BOTOX® pivotal trials for urinary incontinence (UI) due to NDO, more than
  half of all patients were using CIC at baseline1
• BOTOX® patients must be willing and able to perform CIC to empty the bladder4

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

IMPORTANT SAFETY INFORMATION (cont.)
CONTRAINDICATIONS
BOTOX® is contraindicated in the presence of infection at the proposed injection site(s) and in individuals with
known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation.
Intradetrusor injection of BOTOX® is contraindicated in patients with detrusor overactivity associated with a
neurologic condition who have acute urinary tract infection, and in patients with acute urinary retention who
are not routinely performing clean intermittent self-catheterization (CIC).
WARNINGS AND 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.
Spread of Toxin Effect
See Boxed Warning.

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

                                                     2
Phase 3 Trials Study Design

Two double-blind, placebo-controlled, randomized, multicenter studies4:
  Key patient characteristics

  • Adults with UI due to detrusor overactivity associated with a neurologic condition4
     – Diagnosed with MS (n=381)* or SCI (n=310)1,4†
  • Spontaneously voiding or using catheterization4
     – 4.5 daily UI episodes (about 32/week) on average at baseline1
  • Had an inadequate response to or were intolerant of an anticholinergic medication4

Study methodology
     • 691 patients in 2 studies (study 1, n=416; study 2, n=275) were randomized (1:1:1)
       into one of 3 arms: placebo, BOTOX® 200 U, or BOTOX® 300 U1

                      Patients evaluated in the clinic at weeks 2, 6, and 12
Treatment             First treatment                  Starting at week 12, one retreatment                    Each study was at least
regimen1              given at 0 weeks                 permitted based on patient qualification‡               52 weeks in duration

                  0    2                       12                                                                                    52
                               Week 6:
                           Primary timepoint

  Primary efficacy endpoint4                              Select secondary efficacy endpoints4
                                                          • Maximum cystometric capacity (MCC)
  • Weekly UI episodes
                                                          •M
                                                            aximum detrusor pressure (MDP) during first
                                                           involuntary detrusor contraction (IDC)

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

* Mean baseline Expanded Disability Status Scale (EDSS) score of 5.11 (EDSS score of 5.0 = ambulatory
  without aid or rest for approximately 200 m; disability severe enough to impair full day activities).5
† Neurologic injury was at or below thoracic level (T1).3 68% of SCI patients were classified as ASIA A1:
  complete SCI with no motor or sensory function preserved in the sacral segments S4-S5.6
‡ Patient qualification for retreatment was based on loss of effect on incontinent episode frequency: 50% of
  effect in study 1; 70% of effect in study 2. Patients could not qualify for retreatment before week 12.1,4

                                                                                3
BOTOX® Significantly Reduced UI Episodes

Treatment with BOTOX® 200 U reduced weekly mean UI episodes by up to 67%
(-22 episodes) from baseline at week 61,4
                                                  • Placebo: up to 36% reduction (-13 episodes)

Mean change from baseline in weekly number of UI episodes1,4‡
                                                                      Primary                                                 Primary
                                                  Study 1            timepoint
                                                                                                        Study 2              timepoint
                                              0
                                                                                 Placebo (n=146)                                         Placebo (n=91)
                                                                                 BOTOX® 200 U (n=134)                                    BOTOX® 200 U (n=91)
Mean change from baseline (episodes/week)

                                             -5

                                                                      32%
                                            -10
                                                                       -9
                                                                                                                              36%
                                            -15                                                                               -13

                                                        †
                                            -20                       66%
                                                                                                                †             67%
                                                                                                   *                                                      †
                                                      * P
BOTOX® Delivered Long-lasting Response

BOTOX® patients experienced a median 10-month duration of response
(up to 48 weeks) based on patient qualification for retreatment4
      • Placebo: median of 4 months (up to 18 weeks)
Duration of response: time to patient qualification for retreatment1,4
                                                             Study 1                                                         Study 2
                                                       100
                                                                                                Placebo (n=149)                                                    Placebo (n=92)
Percentage of patients not qualified for retreatment

                                                                                                BOTOX® 200 U (n=135)                                               BOTOX® 200 U (n=92)
                                                        80

                                                        60

                                                        40

                                                        20

                                                         0
                                                             0            90              180   270           360      450   0                100         200          300          400

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

                                                                  Starting at week 12,                                            Starting at week 12,
                                                                 patients could qualify                                          patients could qualify
                                                                    for retreatment4                                                for retreatment4

Retreatment qualification criteria 1, 4
                                                             • A minimum of 12 weeks had elapsed since the first treatment
                                                             • The patient requested treatment and met a UI threshold at time of request
                                                               – A return to more than 50% of baseline UI episodes in study 1
                                                               – A return to more than 70% of baseline UI episodes in study 2
IMPORTANT SAFETY INFORMATION (cont.)
WARNINGS AND PRECAUTIONS (cont.)
Autonomic Dysreflexia and Urinary Retention in Patients Treated for Detrusor Overactivity Associated
With a Neurologic Condition
Autonomic dysreflexia associated with intradetrusor injections of BOTOX® could occur in patients treated
for detrusor overactivity associated with a neurologic condition and may require prompt medical therapy. In
clinical trials, the incidence of autonomic dysreflexia was greater in patients treated with BOTOX® 200 Units
compared with placebo (1.5% versus 0.4%, respectively).
In clinical trials, 30.6% of patients (33/108) who were not using clean intermittent catheterization (CIC) prior
to injection, required catheterization for urinary retention following treatment with BOTOX® 200 Units as
compared to 6.7% of patients (7/104) treated with placebo. The median duration
of post-injection catheterization for these patients treated with BOTOX® 200 Units
(n=108) was 289 days (minimum 1 day to maximum 530 days) as compared to a
median duration of 358 days (minimum 2 days to maximum 379 days) for patients
receiving placebo (n=104).
Please see additional Important Safety Information on the following pages.
Please see accompanying full Prescribing Information, including Boxed Warning.

                                                                                                                                          5
BOTOX® Significantly Increased Cystometric Capacity

BOTOX® patients showed a mean increase in maximum cystometric
capacity of up to 63% (+150.8 mL) at week 64
          • Placebo: up to 5% (+12.1 mL)
Maximum cystometric capacity at baseline and week 64†
Study 1                                                                      Study 2

   Placebo (n=129)                                                            Placebo (n=85)

       259.1 mL
                           +5%                271.2 mL                            253.8 mL
                                                                                                        +1%       256.6 mL
                          +12.1 mL                                                                      +2.8 mL

          Baseline                                Week 6                            Baseline                        Week 6

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

                        +54%                                                                      +63%
    253.8 mL                                 389.7 mL                           239.6 mL                          390.4 mL
                      +135.9 mL*                                                                 +150.8 mL*

       Baseline                                                                    Baseline
                                                  Week 6
  * P
BOTOX® Significantly Reduced Detrusor Pressure

BOTOX® patients showed a mean reduction in maximum detrusor pressure at
the first involuntary detrusor contraction of up to 45% (-28.1 cmH20) at week 64
                                          • Placebo: up to 6% (-3.7 cmH20)
Mean change in maximum detrusor pressure during first involuntary
detrusor contraction at week 61,4†
                                          Study 1                                             Study 2
                                    20
                                                                        Placebo (n=103)                                      Placebo (n=68)
                                                                        BOTOX® 200 U (n=41)                                  BOTOX® 200 U (n=29)
                                    10                                                                              5%
                                              BOTOX       ®
                                                                                                     BOTOX     ®
                                                                                                                   +2.1
Mean change from baseline (cmH2O)

                                               200 U          Placebo                                 200 U
                                      0
                                                              -3.7                                                 Placebo

                                    -10
                                                               6%

                                    -20
                                                      *                                                    *
                                               -28.1                                                 -28.7
                                    -30
                                                45%                                                   44%
                                           * P
Most Commonly Reported AEs and Patient CIC Usage

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

                                                  BOTOX® 200 U                     Placebo
   Adverse reactions
                                                         (n=262)                     (n=272)

   Urinary tract infection (UTI)                        64 (24%)                    47 (17%)                • UTI was not required to be
                                                                                                              symptomatic; it was defined
   Urinary retention                                    45 (17%)                     8 (3%)                   as a positive urine culture1
                                                                                                            • Urinary retention was not
   Hematuria                                             10 (4%)                     8 (3%)
                                                                                                              defined and was determined
   Fatigue                                               10 (4%)                     3 (1%)                   at the discretion of the
                                                                                                              investigator1
   Insomnia                                               4 (2%)                     0 (0%)
   Es reported by ≥2% of BOTOX® treated patients and more frequent than in placebo-treated patients in the first 12 weeks after intradetrusor injection in
* A
  double-blind, placebo-controlled trials.4
† During the complete treatment cycle (median duration of 44 weeks of exposure) following initial injection and prior to reinjection, the BOTOX® 200 U
   arm experienced UTI (49%), urinary retention (17%), fatigue (6%), constipation (4%), muscular weakness (4%), dysuria (4%), fall (3%), gait disturbance
   (3%), insomnia (3%), and muscle spasm (2%).4

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

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

   Timepoint                                                   BOTOX® 200 U                                  Placebo
   CIC prior to treatment*                                     119/227 (52.4%)                          139/241 (57.7%)
   CIC initiated at any time during
                                                                33/108 (30.6%)                             7/104 (6.7%)
   complete treatment cycle†
* CIC status during the baseline period.
† Catheterizing for urinary retention.

• In the clinical trials, CIC was initiated at the discretion of the investigator1
• In patients who are not catheterizing, post-void residual (PVR) urine volume should be
  assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks.
  Catheterization should be instituted if PVR urine volume exceeds 200 mL and continued until PVR
  falls below 200 mL. Patients should be instructed to contact their physician if they experience
  difficulty in voiding, as catheterization may be required4

IMPORTANT SAFETY INFORMATION (cont.)
ADVERSE REACTIONS (cont.)
Detrusor Overactivity Associated With a Neurologic Condition (cont.)
The following adverse event rates were reported at any time following initial injection and prior to
reinjection or study exit (median duration of 44 weeks of exposure): urinary tract infections (49%),
urinary retention (17%), fatigue (6%), constipation (4%), muscular weakness (4%), dysuria (4%),
fall (3%), gait disturbance (3%), insomnia (3%), and muscle spasm (2%).

Please see additional Important Safety Information on the following pages.

                                                                             8
The BOTOX® Procedure Can Be Completed In-office

Dosing and administration for the treatment of neurogenic detrusor overactivity
Pretreatment4
     • Prophylactic antibiotics (except aminoglycosides) 1 to 3 days pretreatment
     • Patients should discontinue antiplatelet therapy at least 3 days before the injection
       procedure; patients on anticoagulant therapy need to be managed appropriately to decrease
       the risk of bleeding
     • Reconstitute 200 U of BOTOX® per label; use immediately after reconstitution in the syringe
     • Patients must be asymptomatic for UTI at the time of treatment; BOTOX® treatment is
       contraindicated in the setting of an acute UTI

Treatment4
     • Patient options for anesthesia should be discussed: no anesthesia, local anesthetic with or
       without sedation, or general anesthesia
     • Administer prophylactic antibiotics (except aminoglycosides) on the day of treatment
     • Recommended dose for NDO is 200 U BOTOX® as 1-cc (~6.7 U) injections and should
       not be exceeded
     • In treating adult patients for one or more indications, the maximum cumulative dose
       should generally not exceed 360 U in a 3-month interval
     • Use caution when BOTOX® treatment is used in the presence of inflammation at the
       proposed injection site(s) or when excessive weakness or atrophy is present in
       the target muscle(s)
     • Instill the bladder with enough saline to achieve adequate visualization; overdistention
       should be avoided
     • The injection needle should be filled (primed) with approximately 1 mL of reconstituted
       BOTOX® prior to the start of the injections (depending on needle length) to remove any air

       1   Using a flexible or rigid cystoscope, insert needle                                      Dome

           approximately 2 mm into the detrusor                                                 Injection sites
           (avoiding the trigone)
                                                                                      2
       2   Space injections approximately 1 cm apart
           Administer 30 injections of 1 cc each (30 cc total),
           evenly distributed across the detrusor                                              Opening of left ureter
                                                                     Bladder

           – If you encounter a small amount of bleeding                                                 1
                                                                      base

                                                                                          Trigone
             from an injection site, it should not interfere with
             the procedure1
           – For the final injection, inject approximately 1 mL of sterile
             normal saline so the full dose is delivered
The dosing and administration of BOTOX® is a detailed process. The information
on this page and the following page contain highlights only and are not meant to
be a substitute for appropriate training or review of full Prescribing Information.
Please see additional Important Safety Information on the following pages.
Please see accompanying full Prescribing Information, including Boxed Warning.

                                                         9
Post-treatment Protocol

  30 mins             Immediately postinjection
                      Immediately drain the saline used for bladder wall visualization4
 1-3 days

                      30 minutes postinjection
                      Observe the patient for at least 30 minutes postinjection4
  2 weeks             • D
                         uring this period, safety monitoring and assessments should be done according to your
                        facility’s accepted practices (eg, monitoring of blood pressure, pulse rate, and ensuring the
                        patient has emptied the bladder before leaving the site) 1

                      one to 3 days postInjection
                      One to 3 days after treatment, provide postprocedural prophylactic antibiotics
                      (except aminoglycosides)4

                      2 to 12 weeks postinjection
                      Assess PVR volume within 2 weeks post-treatment (or earlier as medically
 12 weeks             appropriate) for patients who are not catheterizing4
                      Continue to assess PVR volume periodically as medically appropriate up to
                      12 weeks post-treatment4

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

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

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

                                                         10
Coverage and Reimbursement

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

Established J-code for BOTOX® for over 20 years1
• J-code = J0585
• Acquisition cost for 200 U = $1050

Selecting a procedural code is a clinical decision
• Currently no specific CPT® code exists for BOTOX® bladder injections
• AUA states that in absence of an established code, CPT code 53899 (unlisted procedure, urinary system)
  may be used

Simplify reimbursement with Allergan resources
BOTOX® Reimbursement Solutions
        • 20 years of experience in BOTOX® reimbursement for therapeutic uses
        • Provides urology offices with comprehensive support for insurance
          verification, prior authorization, and claims appeals
        • Verification of coverage and benefits for each of your patients
        • Click on BOTOXReimbursementSolutions.com for a wide range of online tools
        • Call the BOTOX® Reimbursement Solutions Support Center at
          1-800-44-BOTOX (1-800-442-6869), Option 4, for direct access to Reimbursement Counselors

Reimbursement Business Managers
        • On-site education, training, and support
        • Knowledge of your local payers’ policies
        • Use the Reimbursement Business Manager Lookup feature at
          BOTOXReimbursementSolutions.com

IMPORTANT SAFETY INFORMATION (cont.)
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 potentiated.
Use of anticholinergic drugs after administration of BOTOX® may potentiate
systemic anticholinergic effects.

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

                                                       11
BOTOX
                                                           ®

DELIVERS.

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

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

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

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

Please see accompanying full Prescribing Information, including Boxed Warning.
* Patient qualification for retreatment was based on loss of effect on incontinent episode frequency: 50% of effect in study 1;
  70% of effect in study 2. Patients could not qualify for retreatment before week 12.1,4

References:
1. Data on file, Allergan, Inc. 2. Fynewever TL, Siddigh S. Management of detrusor overactivity. In: Siddighi S, Hardesty JS, eds. Urogynecology and
Female Pelvic Reconstructive Surgery: Just the Facts. New York, NY: McGraw-Hill; 2006:169-176. 3. Manack A, et al. Neurourol Urodyn. 2011;30(3):
395-401. 4. BOTOX® Prescribing Information, November 2011. 5. Kurtzke Expanded Disability Status Scale. 6. American Spinal Injury Association
(ASIA). Available at: www.asia-spinalinjury.org/publications/59544_sc_Exam_Sheet_r4.pdf. Accessed January 4, 2012. 7. Managed Markets Insight
& Technology, LLC, as of December 2011.
CPT is a registered trademark of the American Medical Association.
©2012 Allergan, Inc., Irvine, CA 92612 ® marks owned by Allergan, Inc.
www.BOTOXMedical.com/HCP 1-800-44-BOTOX APC74IY12 ALBNUI50285
HIGHLIGHTS OF PRESCRIBING INFORMATION                                                •U  pper Limb Spasticity: Select dose based on muscles affected, severity
These highlights do not include all the information needed to use                       of muscle activity, prior response to treatment, and adverse event history;
BOTOX® safely and effectively. See full prescribing information                         Electromyographic guidance recommended (2.5)
for BOTOX.                                                                           • Cervical Dystonia: Base dosing on the patient’s head and neck position,
BOTOX (onabotulinumtoxinA) for injection, for intramuscular,                            localization of pain, muscle hypertrophy, patient response, and adverse
intradetrusor, or intradermal use                                                       event history; use lower initial dose in botulinum toxin naïve patients (2.6)
Initial U.S. Approval: 1989                                                          • Axillary Hyperhidrosis: 50 Units per axilla (2.7)
                                                                                     • Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected
             WARNING: DISTANT SPREAD OF TOXIN EFFECT                                    eye (2.8)
 See full prescribing information for complete boxed warning.                        • Strabismus: 1.25 Units-2.5 Units initially in any one muscle (2.9)
 The effects of BOTOX and all botulinum toxin products may spread                                            DOSAGE FORMS AND STRENGTHS
 from the area of injection to produce symptoms consistent with                      Single-use, sterile 100 Units or 200 Units vacuum-dried powder for
 botulinum toxin effects. These symptoms have been reported hours                    reconstitution only with sterile, non-preserved 0.9% Sodium Chloride
 to weeks after injection. Swallowing and breathing difficulties can                 Injection USP prior to injection (3)
 be life threatening and there have been reports of death. The risk of
                                                                                                                    CONTRAINDICATIONS
 symptoms is probably greatest in children treated for spasticity but
                                                                                     • Hypersensitivity to any botulinum toxin preparation or to any of the
 symptoms can also occur in adults, particularly in those patients
                                                                                        components in the formulation (4.1, 5.4, 6)
 who have an underlying condition that would predispose them to
                                                                                     • Infection at the proposed injection site (4.2)
 these symptoms. (5.2)
                                                                                     • Intradetrusor Injections: Acute Urinary Tract Infection and/or Acute
                          RECENT MAJOR CHANGES                                          Urinary Retention (4.3)
• Indications and Usage, Detrusor Overactivity associated with a Neurologic                                  WARNINGS AND PRECAUTIONS
   Condition (1.1) 8/2011                                                            • Potency Units of BOTOX not interchangeable with other preparations
• Dosage and Administration, Detrusor Overactivity associated with a                   of botulinum toxin products (5.1, 11)
   Neurologic Condition (2.3) 8/2011                                                 • Spread of toxin effects; swallowing and breathing difficulties can lead
• Contraindications, Acute Urinary Tract Infection and Acute Urinary                   to death. Seek immediate medical attention if respiratory, speech
   Retention (4.3) 8/2011                                                               or swallowing difficulties occur (5.2, 5.5)
• Warnings and Precautions, Injections In or Near Vulnerable Anatomic               • Care should be taken when injecting in or near vulnerable anatomic
   Structures (5.3) 11/2011                                                             structures (5.3)
• Warnings and Precautions, Autonomic Dysreflexia and Urinary Retention             • Concomitant neuromuscular disorder may exacerbate clinical effects
   in Patients Treated for Detrusor Overactivity associated with a Neurologic           of treatment (5.6)
   Condition (5.11) 8/2011                                                           • Use with caution in patients with compromised respiratory function
                           INDICATIONS AND USAGE                                        (5.5, 5.7, 5.10)
BOTOX is an acetylcholine release inhibitor and a neuromuscular blocking             • Corneal exposure and ulceration due to reduced blinking may occur
agent indicated for:                                                                    with BOTOX treatment of blepharospasm (5.8)
• Treatment of urinary incontinence due to detrusor overactivity associated         • Retrobulbar hemorrhages and compromised retinal circulation may occur
   with a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis      with BOTOX treatment of strabismus (5.9)
   (MS)] in adults who have an inadequate response to or are intolerant of           • Bronchitis and upper respiratory tract infections in patients treated
   an anticholinergic medication (1.1)                                                  for upper limb spasticity (5.10)
• Prophylaxis of headaches in adult patients with chronic migraine (≥15 days        • Urinary retention: Post-void residual urine volume should be monitored
   per month with headache lasting 4 hours a day or longer) (1.2)                       in patients treated for detrusor overactivity associated with a neurologic
• Treatment of upper limb spasticity in adult patients (1.3)                            condition who do not catheterize routinely, particularly patients with MS.
• Treatment of cervical dystonia in adult patients, to reduce the severity             (5.11)
   of abnormal head position and neck pain (1.4)                                                                    ADVERSE REACTIONS
• Treatment of severe axillary hyperhidrosis that is inadequately managed           The most common adverse reactions (≥5% and >placebo) are (6.1):
   by topical agents in adult patients (1.5)                                         • Detrusor Overactivity associated with a neurologic condition: urinary
• Treatment of blepharospasm associated with dystonia in patients ≥12 years            tract infection, urinary retention
   of age (1.6)                                                                      • Chronic Migraine: neck pain, headache
• Treatment of strabismus in patients ≥12 years of age (1.6)                         • Spasticity: pain in extremity
Important limitations:                                                               • Cervical Dystonia: dysphagia, upper respiratory infection, neck pain,
• Safety and effectiveness of BOTOX have not been established for the                 headache, increased cough, flu syndrome, back pain, rhinitis
   prophylaxis of episodic migraine (14 headache days or fewer per month).           • Axillary Hyperhidrosis: injection site pain and hemorrhage, non-axillary
   (1.2)                                                                                sweating, pharyngitis, flu syndrome
• Safety and effectiveness of BOTOX have not been established for                   To report SUSPECTED ADVERSE REACTIONS, contact Allergan at
   the treatment of upper limb spasticity in pediatric patients, and for the         1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
   treatment of lower limb spasticity in adult and pediatric patients. (1.3)                                        DRUG INTERACTIONS
• Safety and effectiveness of BOTOX for hyperhidrosis in body areas other           • Patients receiving concomitant treatment of BOTOX and aminoglycosides
   than axillary have not been established. (1.5)                                       or other agents interfering with neuromuscular transmission (e.g., curare-
                        DOSAGE AND ADMINISTRATION                                       like agents), or muscle relaxants, should be observed closely because the
• Indication specific dosage and administration recommendations should                 effect of BOTOX may be potentiated (7)
   be followed; Do not exceed a total dose of 360 Units administered in                                       USE IN SPECIFIC POPULATIONS
   a 3 month interval (2.1)                                                          • Pregnancy: Based on animal data, may cause fetal harm (8.1)
• See Preparation and Dilution Technique for instructions on BOTOX                  • Pediatric Use: Safety and efficacy are not established in patients under
   reconstitution, storage, and preparation before injection (2.2)                      18 years of age for the prophylaxis of headaches in chronic migraine, the
• Detrusor Overactivity associated with a Neurologic Condition:                        treatment of detrusor overactivity associated with a neurologic condition,
   Recommended total dose 200 Units, as 1 mL (~6.7 Units) injections                    upper limb spasticity, and axillary hyperhidrosis, in patients under 16 years
   across 30 sites into the detrusor (2.3)                                              of age for the treatment of cervical dystonia, and in patients under 12 years
• Chronic Migraine: Recommended total dose 155 Units, as 0.1 mL (5 Units)              of age for the treatment of blepharospasm and strabismus (8.4)
   injections per each site divided across 7 head/neck muscles (2.4)
                                                                                     See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
                                                                                                                                    Revised: 11/2011

FULL PRESCRIBING INFORMATION: CONTENTS*                                                2.3 Detrusor Overactivity associated with a Neurologic Condition
WARNING: DISTANT SPREAD OF TOXIN EFFECT                                                2.4 Chronic Migraine
1 INDICATIONS AND USAGE                                                                2.5 Upper Limb Spasticity
  1.1  Detrusor Overactivity associated with a Neurologic Condition                    2.6 Cervical Dystonia
  1.2  Chronic Migraine                                                                2.7 Primary Axillary Hyperhidrosis
  1.3  Upper Limb Spasticity                                                           2.8 Blepharospasm
  1.4  Cervical Dystonia                                                               2.9 Strabismus
  1.5  Primary Axillary Hyperhidrosis                                                3 DOSAGE FORMS AND STRENGTHS
  1.6  Blepharospasm and Strabismus                                                  4 CONTRAINDICATIONS
2 DOSAGE AND ADMINISTRATION                                                            4.1 Known Hypersensitivity to Botulinum Toxin
  2.1 Instructions for Safe Use                                                        4.2 Infection at the Injection Site(s)
  2.2 Preparation and Dilution Technique                                               4.3 Acute Urinary Tract Infection and/or Acute Urinary Retention
5 WARNINGS AND PRECAUTIONS                                                            8.4 Pediatric Use
  5.1 Lack of Interchangeability between Botulinum Toxin Products                     8.5 Geriatric Use
  5.2 Spread of Toxin Effect                                                        10 OVERDOSAGE
  5.3 Injections In or Near Vulnerable Anatomic Structures                          11 DESCRIPTION
  5.4 Hypersensitivity Reactions                                                    12 CLINICAL PHARMACOLOGY
  5.5 Dysphagia and Breathing Difficulties in Treatment of Cervical Dystonia         12.1 Mechanism of Action
  5.6 Pre-Existing Neuromuscular Disorders                                            12.3 Pharmacokinetics
  5.7 Pulmonary Effects of BOTOX in Patients with Compromised                      13 NONCLINICAL TOXICOLOGY
        Respiratory Status Treated for Spasticity or for Detrusor Overactivity        13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
        associated with a Neurologic Condition                                        13.2 Animal Toxicology
  5.8 Corneal Exposure and Ulceration in Patients Treated with BOTOX               14 CLINICAL STUDIES
        for Blepharospasm                                                             14.1 Detrusor Overactivity associated with a Neurologic Condition
  5.9 Retrobulbar Hemorrhages in Patients Treated with BOTOX                         14.2 Chronic Migraine
        for Strabismus                                                                14.3 Upper Limb Spasticity
  5.10 Bronchitis and Upper Respiratory Tract Infections in Patients Treated         14.4 Cervical Dystonia
        for Spasticity                                                                14.5 Primary Axillary Hyperhidrosis
  5.11 Autonomic Dysreflexia and Urinary Retention in Patients Treated               14.6 Blepharospasm
        for Detrusor Overactivity associated with a Neurologic Condition              14.7 Strabismus
  5.12 Human Albumin and Transmission of Viral Diseases                             16 HOW SUPPLIED/STORAGE AND HANDLING
6 ADVERSE REACTIONS                                                                 17 PATIENT COUNSELING INFORMATION
  6.1 Clinical Trials Experience                                                      17.1 Swallowing, Speaking or Breathing Difficulties, or Other
  6.2 Immunogenicity                                                                        Unusual Symptoms
  6.3 Post-Marketing Experience                                                       17.2 Ability to Operate Machinery or Vehicles
7 DRUG INTERACTIONS                                                                   17.3 Voiding Difficulties after Bladder Injections
8 USE IN SPECIFIC POPULATIONS
  8.1 Pregnancy                                                                     * Sections or subsections omitted from the full prescribing information
  8.3 Nursing Mothers                                                                 are not listed

FULL PRESCRIBING INFORMATION                                                        1.5 Primary Axillary Hyperhidrosis
                                                                                    BOTOX is indicated for the treatment of severe primary axillary hyperhidrosis
             WARNING: DISTANT SPREAD OF TOXIN EFFECT                                that is inadequately managed with topical agents.
 Postmarketing reports indicate that the effects of BOTOX and all
 botulinum toxin products may spread from the area of injection to                  Important limitations
 produce symptoms consistent with botulinum toxin effects. These                    The safety and effectiveness of BOTOX for hyperhidrosis in other body areas
 may include asthenia, generalized muscle weakness, diplopia,                       have not been established. Weakness of hand muscles and blepharoptosis
 ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and                 may occur in patients who receive BOTOX for palmar hyperhidrosis and facial
 breathing difficulties. These symptoms have been reported hours                    hyperhidrosis, respectively. Patients should be evaluated for potential causes
 to weeks after injection. Swallowing and breathing difficulties can                of secondary hyperhidrosis (e.g., hyperthyroidism) to avoid symptomatic
 be life threatening and there have been reports of death. The risk of              treatment of hyperhidrosis without the diagnosis and/or treatment of the
 symptoms is probably greatest in children treated for spasticity but               underlying disease.
 symptoms can also occur in adults treated for spasticity and other                 Safety and effectiveness of BOTOX have not been established for the
 conditions, particularly in those patients who have an underlying                  treatment of axillary hyperhidrosis in pediatric patients under age 18.
 condition that would predispose them to these symptoms. In
                                                                                    1.6 Blepharospasm and Strabismus
 unapproved uses, including spasticity in children, and in approved
                                                                                    BOTOX is indicated for the treatment of strabismus and blepharospasm
 indications, cases of spread of effect have been reported at doses
                                                                                    associated with dystonia, including benign essential blepharospasm
 comparable to those used to treat cervical dystonia and at lower
                                                                                    or VII nerve disorders in patients 12 years of age and above.
 doses. [See Warnings and Precautions (5.2)]
                                                                                    2      DOSAGE AND ADMINISTRATION
1     INDICATIONS AND USAGE                                                         2.1 Instructions for Safe Use
1.1 Detrusor Overactivity associated with a Neurologic Condition                    The potency Units of BOTOX (onabotulinumtoxinA) for injection are
BOTOX (onabotulinumtoxinA) for injection is indicated for the treatment of          specific to the preparation and assay method utilized. They are not
urinary incontinence due to detrusor overactivity associated with a neurologic      interchangeable with other preparations of botulinum toxin products
condition (e.g., SCI, MS) in adults who have an inadequate response to or are       and, therefore, units of biological activity of BOTOX cannot be compared
intolerant of an anticholinergic medication.                                        to nor converted into units of any other botulinum toxin products
1.2 Chronic Migraine                                                                assessed with any other specific assay method [see Warnings and
BOTOX is indicated for the prophylaxis of headaches in adult patients with          Precautions (5.1) and Description (11)].
chronic migraine (≥15 days per month with headache lasting 4 hours a day            Indication specific dosage and administration recommendations should be
or longer).                                                                         followed. In treating adult patients for one or more indications, the maximum
Important limitations                                                               cumulative dose should generally not exceed 360 Units, in a 3 month interval.
Safety and effectiveness have not been established for the prophylaxis              The safe and effective use of BOTOX depends upon proper storage
of episodic migraine (14 headache days or fewer per month) in seven                 of the product, selection of the correct dose, and proper reconstitution
placebo-controlled studies.                                                         and administration techniques. Physicians administering BOTOX must
1.3 Upper Limb Spasticity                                                           understand the relevant neuromuscular and/or orbital anatomy of the area
BOTOX is indicated for the treatment of upper limb spasticity in adult patients,    involved and any alterations to the anatomy due to prior surgical procedures.
to decrease the severity of increased muscle tone in elbow flexors (biceps),        An understanding of standard electromyographic techniques is also required
wrist flexors (flexor carpi radialis and flexor carpi ulnaris) and finger flexors   for treatment of strabismus and of upper limb spasticity, and may be useful
(flexor digitorum profundus and flexor digitorum sublimis).                         for the treatment of cervical dystonia.
Important limitations                                                               Use caution when BOTOX treatment is used in the presence of inflammation
Safety and effectiveness of BOTOX have not been established for the                 at the proposed injection site(s) or when excessive weakness or atrophy
treatment of other upper limb muscle groups, or for the treatment of lower limb     is present in the target muscle(s).
spasticity. Safety and effectiveness of BOTOX have not been established for         2.2 Preparation and Dilution Technique
the treatment of spasticity in pediatric patients under age 18 years. BOTOX         BOTOX is supplied in single-use 100 Units and 200 Units per vial. Prior
has not been shown to improve upper extremity functional abilities, or range        to injection, reconstitute each vacuum-dried vial of BOTOX with sterile,
of motion at a joint affected by a fixed contracture. Treatment with BOTOX is       non-preserved 0.9% Sodium Chloride Injection USP. Draw up the proper
not intended to substitute for usual standard of care rehabilitation regimens.      amount of diluent in the appropriate size syringe (see Table 1, or for specific
1.4 Cervical Dystonia                                                               instructions for detrusor overactivity associated with a neurologic condition
BOTOX is indicated for the treatment of adults with cervical dystonia,              see Section 2.3), and slowly inject the diluent into the vial. Discard the vial
to reduce the severity of abnormal head position and neck pain associated           if a vacuum does not pull the diluent into the vial. Gently mix BOTOX with
with cervical dystonia.                                                             the saline by rotating the vial. Record the date and time of reconstitution
                                                                                    on the space on the label. BOTOX should be administered within 24 hours
                                                                                    after reconstitution. During this time period, reconstituted BOTOX should
                                                                                    be stored in a refrigerator (2° to 8°C).
Table 1: Dilution Instructions for BOTOX Vials (100 Units and 200 Units)             Figure 1: Injection Pattern for Detrusor Overactivity associated with
                                                                                     a Neurologic Condition
     Diluent*           Resulting             Diluent*            Resulting
    Added to            Dose Units           Added to             Dose Units
   100 Unit Vial        per 0.1 mL          200 Unit Vial         per 0.1 mL

       1 mL               10 Units               1 mL              20 Units
       2 mL                5 Units               2 mL               10 Units
       4 mL               2.5 Units              4 mL               5 Units
       8 mL              1.25 Units              8 mL              2.5 Units
                                                10 mL               2 Units
*Preservative-free 0.9% Sodium Chloride Injection, USP Only
Note: These dilutions are calculated for an injection volume of 0.1 mL. A
decrease or increase in the BOTOX dose is also possible by administering
a smaller or larger injection volume - from 0.05 mL (50% decrease in dose)
to 0.15 mL (50% increase in dose).
An injection of BOTOX is prepared by drawing into an appropriately sized
sterile syringe an amount of the properly reconstituted toxin slightly greater       2.4 Chronic Migraine
than the intended dose. Air bubbles in the syringe barrel are expelled and           The recommended dilution is 200 Units/4 mL or 100 Units/2 mL, with a final
the syringe is attached to an appropriate injection needle. Patency of the           concentration of 5 Units per 0.1 mL (see Table 1). The recommended dose
needle should be confirmed. A new, sterile, needle and syringe should be             for treating chronic migraine is 155 Units administered intramuscularly (IM)
used to enter the vial on each occasion for removal of BOTOX.                        using a sterile 30-gauge, 0.5 inch needle as 0.1 mL (5 Units) injections per
Reconstituted BOTOX should be clear, colorless, and free of particulate              each site. Injections should be divided across 7 specific head/neck muscle
matter. Parenteral drug products should be inspected visually for particulate        areas as specified in the diagrams and Table 2 below. A one inch needle
matter and discoloration prior to administration and whenever the solution           may be needed in the neck region for patients with thick neck muscles. With
and the container permit.                                                            the exception of the procerus muscle, which should be injected at one site
2.3 Detrusor Overactivity associated with a Neurologic Condition                     (midline), all muscles should be injected bilaterally with half the number of
Patients should not have an acute urinary tract infection prior to treatment.        injection sites administered to the left, and half to the right side of the head
Prophylactic antibiotics (except aminoglycosides, see Drug Interactions (7))         and neck. The recommended re-treatment schedule is every 12 weeks.
should be administered 1-3 days pre-treatment, on the treatment day, and             Diagrams 1-4: Recommended Injection Sites (A thru G) for Chronic Migraine
1-3 days post-treatment.
                                                                                                 1                    2                      3                    4
Patients should discontinue anti-platelet therapy at least 3 days before
the injection procedure. Patients on anti-coagulant therapy need to be
managed appropriately to decrease the risk of bleeding.
Appropriate caution should be exercised when performing a cystoscopy.
An intravesical instillation of diluted local anesthetic with or without sedation,
or general anesthesia may be used prior to injection, per local site practice.
If a local anesthetic instillation is performed, the bladder should be drained
and irrigated with sterile saline before injection.
The recommended dose is 200 Units of BOTOX per treatment, and should                     A. Corrugator:        . Temporalis:
                                                                                                              D                      . Occipitalis:
                                                                                                                                    E                     . Cervical
                                                                                                                                                         F
not be exceeded.                                                                         5 U each side        20 U each side        15 U each side       paraspinal:
                                                                                                                                                         10 U each side
Reconstitute a 200 Unit vial of BOTOX with 6 mL of 0.9% non-preserved
saline solution and mix the vial gently. Draw 2 mL from the vial into each               B. Procerus:                                                    G. Trapezius:
                                                                                         5 U (one site)                                                  15 U each side
of three 10 mL syringes. Complete the reconstitution by adding 8 mL of
0.9% non-preserved saline solution into each of the 10 mL syringes, and                  C. Frontalis:
mix gently. This will result in three 10 mL syringes each containing 10 mL               10 U each side
(~67 Units in each), for a total of 200 Units of reconstituted BOTOX. Use
immediately after reconstitution in the syringe. Dispose of any unused saline.       Table 2: BOTOX Dosing by Muscle for Chronic Migraine
Alternatively, reconstitute two 100 Unit vials of BOTOX, each with 6 mL of
                                                                                                                                           Recommended Dose
0.9% non-preserved saline solution and mix the vials gently. Draw 4 mL from              Head/Neck Area
                                                                                                                                            (Number of Sitesa)
each vial into each of two 10 mL syringes. Draw the remaining 2 mL from
each vial into a third 10 mL syringe. Complete the reconstitution by adding              Frontalisb                                 20 Units divided in 4 sites
6 mL of 0.9% non-preserved saline solution into each of the 10 mL syringes,
and mix gently. This will result in three 10 mL syringes each containing 10 mL           Corrugator       b
                                                                                                                                    10 Units divided in 2 sites
(~67 Units in each), for a total of 200 Units of reconstituted BOTOX. Use
immediately after reconstitution in the syringe. Dispose of any unused saline.           Procerus                                   5 Units in 1 site
Reconstituted BOTOX (200 Units/30 mL) is injected into the detrusor
                                                                                         Occipitalis  b
                                                                                                                                    30 Units divided in 6 sites
muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder
should be instilled with enough saline to achieve adequate visualization                 Temporalis       b
                                                                                                                                    40 Units divided in 8 sites
for the injections, but over-distension should be avoided.
The injection needle should be filled (primed) with approximately 1 mL                   Trapezius    b
                                                                                                                                    30 Units divided in 6 sites
of reconstituted BOTOX prior to the start of injections (depending on the
                                                                                         Cervical Paraspinal Muscle Group       b
                                                                                                                                    20 Units divided in 4 sites
needle length) to remove any air.
The needle should be inserted approximately 2 mm into the detrusor,                      Total Dose:                                155 Units divided in 31 sites
and 30 injections of 1 mL (~6.7 Units) each (total volume of 30 mL) should           a
                                                                                       Each IM injection site = 0.1 mL = 5 Units BOTOX
be spaced approximately 1 cm apart (see Figure 1). For the final injection,          b
                                                                                       Dose distributed bilaterally
approximately 1 mL of sterile normal saline should be injected so the full
dose is delivered. After the injections are given, the saline used for bladder       2.5 Upper Limb Spasticity
wall visualization should be drained. The patient should be observed for             Dosing in initial and sequential treatment sessions should be tailored to the
at least 30 minutes post-injection.                                                  individual based on the size, number and location of muscles involved, severity
                                                                                     of spasticity, the presence of local muscle weakness, the patient’s response
Patients should be considered for re-injection when the clinical effect of the       to previous treatment, or adverse event history with BOTOX. In clinical trials,
previous injection diminishes (median time to qualification for re-treatment         doses ranging from 75 Units to 360 Units were divided among selected
in the double-blind, placebo-controlled clinical studies was 295-337 days            muscles at a given treatment session.
[42-48 weeks] for BOTOX 200 Units), but no sooner than 12 weeks from
the prior bladder injection.
Table 3: BOTOX Dosing by Muscle for Upper Limb Spasticity                            Figure 2: Injection Pattern for Primary Axillary Hyperhidrosis
                                                Recommended Dose
 Muscle
                                           Total Dosage (Number of Sites)

 Biceps Brachii                         100 Units-200 Units divided in 4 sites

 Flexor Carpi Radialis                  12.5 Units-50 Units in 1 site
                                                                                     Each dose is injected to a depth of approximately 2 mm and at a 45° angle
 Flexor Carpi Ulnaris                   12.5 Units-50 Units in 1 site                to the skin surface, with the bevel side up to minimize leakage and to ensure
                                                                                     the injections remain intradermal. If injection sites are marked in ink, do not
 Flexor Digitorum Profundus             30 Units-50 Units in 1 site                  inject BOTOX directly through the ink mark to avoid a permanent tattoo effect.

 Flexor Digitorum Sublimis              30 Units-50 Units in 1 site                  2.8 Blepharospasm
                                                                                     For blepharospasm, reconstituted BOTOX is injected using a sterile, 27-30
The recommended dilution is 200 Units/4 mL or 100 Units/2 mL with 0.9%               gauge needle without electromyographic guidance. The initial recommended
non-preserved sterile saline (see Table 1). The lowest recommended starting          dose is 1.25 Units-2.5 Units (0.05 mL to 0.1 mL volume at each site) injected
dose should be used, and no more than 50 Units per site should generally be          into the medial and lateral pre-tarsal orbicularis oculi of the upper lid and into
administered. An appropriately sized needle (e.g., 25-30 gauge) may be used          the lateral pre-tarsal orbicularis oculi of the lower lid. Avoiding injection near the
for superficial muscles, and a longer 22 gauge needle may be used for deeper         levator palpebrae superioris may reduce the complication of ptosis. Avoiding
musculature. Localization of the involved muscles with electromyographic             medial lower lid injections, and thereby reducing diffusion into the inferior
guidance or nerve stimulation techniques is recommended.                             oblique, may reduce the complication of diplopia. Ecchymosis occurs easily
Repeat BOTOX treatment may be administered when the effect of a previous             in the soft eyelid tissues. This can be prevented by applying pressure at the
injection has diminished, but generally no sooner than 12 weeks after the            injection site immediately after the injection.
previous injection. The degree and pattern of muscle spasticity at the time          The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5
of re-injection may necessitate alterations in the dose of BOTOX and muscles         Units it is 100 Units/4 mL (see Table 1).
to be injected.                                                                      In general, the initial effect of the injections is seen within three days and
2.6 Cervical Dystonia                                                                reaches a peak at one to two weeks post-treatment. Each treatment lasts
A double-blind, placebo-controlled study enrolled patients who had extended          approximately three months, following which the procedure can be repeated.
histories of receiving and tolerating BOTOX injections, with prior individualized    At repeat treatment sessions, the dose may be increased up to two-fold
adjustment of dose. The mean BOTOX dose administered to patients in this             if the response from the initial treatment is considered insufficient, usually
study was 236 Units (25th to 75th percentile range of 198 Units to 300 Units).       defined as an effect that does not last longer than two months. However,
The BOTOX dose was divided among the affected muscles [see Clinical                  there appears to be little benefit obtainable from injecting more than 5 Units
Studies (14.4)].                                                                     per site. Some tolerance may be found when BOTOX is used in treating
                                                                                     blepharospasm if treatments are given any more frequently than every three
Dosing in initial and sequential treatment sessions should be tailored to the
                                                                                     months, and is rare to have the effect be permanent.
individual patient based on the patient’s head and neck position, localization
of pain, muscle hypertrophy, patient response, and adverse event history.            The cumulative dose of BOTOX treatment for blepharospasm in a 30-day
The initial dose for a patient without prior use of BOTOX should be at a             period should not exceed 200 Units.
lower dose, with subsequent dosing adjusted based on individual response.            2.9 Strabismus
Limiting the total dose injected into the sternocleidomastoid muscle to 100          BOTOX is intended for injection into extraocular muscles utilizing the
Units or less may decrease the occurrence of dysphagia [see Warnings and             electrical activity recorded from the tip of the injection needle as a guide
Precautions (5.2, 5.5, 5.6)].                                                        to placement within the target muscle. Injection without surgical exposure
The recommended dilution is 200 Units/2 mL, 200 Units/4 mL, 100 Units/1 mL,          or electromyographic guidance should not be attempted. Physicians should
or 100 Units/2 mL with 0.9% non-preserved sterile saline, depending on volume        be familiar with electromyographic technique.
and number of injection sites desired to achieve treatment objectives (see           To prepare the eye for BOTOX injection, it is recommended that several
Table 1). In general, no more than 50 Units per site should be administered.         drops of a local anesthetic and an ocular decongestant be given several
An appropriately sized needle (e.g., 25-30 gauge) may be used for superficial        minutes prior to injection.
muscles, and a longer 22 gauge needle may be used for deeper musculature.
Localization of the involved muscles with electromyographic guidance may             The volume of BOTOX injected for treatment of strabismus should be
be useful.                                                                           between 0.05-0.15 mL per muscle.
Clinical improvement generally begins within the first two weeks after               The initial listed doses of the reconstituted BOTOX [see Dosage and
injection with maximum clinical benefit at approximately six weeks post-             Administration (2.2)] typically create paralysis of the injected muscles
injection. In the double-blind, placebo-controlled study most subjects               beginning one to two days after injection and increasing in intensity during
were observed to have returned to pre-treatment status by 3 months                   the first week. The paralysis lasts for 2-6 weeks and gradually resolves over
post-treatment.                                                                      a similar time period. Overcorrections lasting over six months have been
                                                                                     rare. About one half of patients will require subsequent doses because
2.7 Primary Axillary Hyperhidrosis                                                   of inadequate paralytic response of the muscle to the initial dose, or because
The recommended dose is 50 Units per axilla. The hyperhidrotic area to               of mechanical factors such as large deviations or restrictions, or because
be injected should be defined using standard staining techniques, e.g.,              of the lack of binocular motor fusion to stabilize the alignment.
Minor’s Iodine-Starch Test. The recommended dilution is 100 Units/4 mL
                                                                                     Initial doses in Units
with 0.9% preservative-free sterile saline (see Dilution Table). Using a 30
                                                                                     Use the lower listed doses for treatment of small deviations. Use the larger
gauge needle, 50 Units of BOTOX (2 mL) is injected intradermally in 0.1
                                                                                     doses only for large deviations.
to 0.2 mL aliquots to each axilla evenly distributed in multiple sites (10-15)
approximately 1-2 cm apart.                                                            • For vertical muscles, and for horizontal strabismus of less than
                                                                                             20 prism diopters: 1.25 Units-2.5 Units in any one muscle.
Repeat injections for hyperhidrosis should be administered when the clinical
effect of a previous injection diminishes.                                             • For horizontal strabismus of 20 prism diopters to 50 prism diopters:
                                                                                             2.5 Units-5 Units in any one muscle.
Instructions for the Minor’s Iodine-Starch Test Procedure:
Patients should shave underarms and abstain from use of over-the-counter               • For persistent VI nerve palsy of one month or longer duration:
deodorants or antiperspirants for 24 hours prior to the test. Patient should be              1.25 Units-2.5 Units in the medial rectus muscle.
resting comfortably without exercise, hot drinks for approximately 30 minutes        Subsequent doses for residual or recurrent strabismus
prior to the test. Dry the underarm area and then immediately paint it with            • It is recommended that patients be re-examined 7-14 days after
iodine solution. Allow the area to dry, then lightly sprinkle the area with starch           each injection to assess the effect of that dose.
powder. Gently blow off any excess starch powder. The hyperhidrotic area will
                                                                                       • Patients experiencing adequate paralysis of the target muscle
develop a deep blue-black color over approximately 10 minutes.
                                                                                             that require subsequent injections should receive a dose comparable
Each injection site has a ring of effect of up to approximately 2 cm in diameter.            to the initial dose.
To minimize the area of no effect, the injection sites should be evenly spaced
                                                                                       • Subsequent doses for patients experiencing incomplete paralysis
as shown in Figure 2.
                                                                                             of the target muscle may be increased up to two-fold compared
                                                                                             to the previously administered dose.
                                                                                       • Subsequent injections should not be administered until the effects
                                                                                             of the previous dose have dissipated as evidenced by substantial
                                                                                             function in the injected and adjacent muscles.
•    he maximum recommended dose as a single injection for any
      T                                                                               5.5 	Dysphagia and Breathing Difficulties in Treatment of
      one muscle is 25 Units.                                                                Cervical Dystonia
The recommended dilution to achieve 1.25 Units is 100 Units/8 mL;                     Treatment with BOTOX and other botulinum toxin products can result in
for 2.5 Units it is 100 Units/4 mL (see Table 1).                                     swallowing or breathing difficulties. Patients with pre-existing swallowing
                                                                                      or breathing difficulties may be more susceptible to these complications.
3     DOSAGE FORMS AND STRENGTHS                                                      In most cases, this is a consequence of weakening of muscles in the area
Single-use, sterile 100 Units or 200 Units vacuum-dried powder for                    of injection that are involved in breathing or swallowing. When distant effects
reconstitution only with sterile, non-preserved 0.9% Sodium Chloride                  occur, additional respiratory muscles may be involved [see Warnings and
Injection USP prior to injection.                                                     Precautions (5.2)].
4     CONTRAINDICATIONS                                                               Deaths as a complication of severe dysphagia have been reported after
4.1 Known Hypersensitivity to Botulinum Toxin                                         treatment with botulinum toxin. Dysphagia may persist for several months,
BOTOX is contraindicated in patients who are hypersensitive to any                    and require use of a feeding tube to maintain adequate nutrition and
botulinum toxin preparation or to any of the components in the formulation            hydration. Aspiration may result from severe dysphagia and is a particular
[see Warnings and Precautions (5.4)].                                                 risk when treating patients in whom swallowing or respiratory function is
4.2 Infection at the Injection Site(s)                                                already compromised.
BOTOX is contraindicated in the presence of infection at the proposed                 Treatment of cervical dystonia with botulinum toxins may weaken neck
injection site(s).                                                                    muscles that serve as accessory muscles of ventilation. This may result in
                                                                                      a critical loss of breathing capacity in patients with respiratory disorders
4.3 Acute Urinary Tract Infection and/or Acute Urinary Retention                      who may have become dependent upon these accessory muscles. There
Intradetrusor injection of BOTOX is contraindicated in patients with detrusor         have been postmarketing reports of serious breathing difficulties, including
overactivity associated with a neurologic condition who have acute urinary            respiratory failure, in cervical dystonia patients.
tract infection, and in patients with acute urinary retention who are not routinely
performing clean intermittent self-catheterization (CIC).                             Patients with smaller neck muscle mass and patients who require bilateral
                                                                                      injections into the sternocleidomastoid muscle have been reported
5    WARNINGS AND PRECAUTIONS                                                         to be at greater risk for dysphagia. Limiting the dose injected into the
5.1 Lack of Interchangeability between Botulinum Toxin Products                       sternocleidomastoid muscle may reduce the occurrence of dysphagia.
The potency Units of BOTOX are specific to the preparation and assay                  Injections into the levator scapulae may be associated with an increased
method utilized. They are not interchangeable with other preparations                 risk of upper respiratory infection and dysphagia.
of botulinum toxin products and, therefore, units of biological activity
                                                                                      Patients treated with botulinum toxin may require immediate medical
of BOTOX cannot be compared to nor converted into units of any other
                                                                                      attention should they develop problems with swallowing, speech or
botulinum toxin products assessed with any other specific assay
                                                                                      respiratory disorders. These reactions can occur within hours to weeks
method [see Dosage and Administration (2.1), Description (11)].
                                                                                      after injection with botulinum toxin [see Warnings and Precautions (5.2)
5.2 Spread of Toxin Effect                                                            and Adverse Reactions (6.1)].
Postmarketing safety data from BOTOX and other approved botulinum toxins
                                                                                      5.6 Pre-Existing Neuromuscular Disorders
suggest that botulinum toxin effects may, in some cases, be observed beyond
                                                                                      Individuals with peripheral motor neuropathic diseases, amyotrophic lateral
the site of local injection. The symptoms are consistent with the mechanism
                                                                                      sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or
of action of botulinum toxin and may include asthenia, generalized muscle
                                                                                      Lambert-Eaton syndrome) should be monitored particularly closely when
weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary
                                                                                      given botulinum toxin. Patients with neuromuscular disorders may be at
incontinence, and breathing difficulties. These symptoms have been reported
                                                                                      increased risk of clinically significant effects including severe dysphagia and
hours to weeks after injection. Swallowing and breathing difficulties can be
                                                                                      respiratory compromise from therapeutic doses of BOTOX [see Adverse
life threatening and there have been reports of death related to spread of
                                                                                      Reactions (6.1)].
toxin effects. The risk of symptoms is probably greatest in children treated for
spasticity but symptoms can also occur in adults treated for spasticity and           5.7 	Pulmonary Effects of BOTOX in Patients with Compromised
other conditions, and particularly in those patients who have an underlying                 Respiratory Status Treated for Spasticity or for Detrusor
condition that would predispose them to these symptoms. In unapproved                       Overactivity associated with a Neurologic Condition
uses, including spasticity in children, and in approved indications, symptoms         Patients with compromised respiratory status treated with BOTOX for upper
consistent with spread of toxin effect have been reported at doses comparable         limb spasticity should be monitored closely. In a double-blind, placebo-
to or lower than doses used to treat cervical dystonia. Patients or caregivers        controlled, parallel group study in patients with stable reduced pulmonary
should be advised to seek immediate medical care if swallowing, speech or             function (defined as FEV1 40-80% of predicted value and FEV1/FVC ≤ 0.75),
respiratory disorders occur.                                                          the event rate in change of Forced Vital Capacity ≥15% or ≥20% was
No definitive serious adverse event reports of distant spread of toxin effect         generally greater in patients treated with BOTOX than in patients treated
associated with dermatologic use of BOTOX/BOTOX® Cosmetic at the                      with placebo (see Table 4).
labeled dose of 20 Units (for glabellar lines) or 100 Units (for severe primary       Table 4: Event rate per patient treatment cycle among patients with
axillary hyperhidrosis) have been reported.                                           reduced lung function who experienced at least a 15% or 20% decrease
No definitive serious adverse event reports of distant spread of toxin effect         in forced vital capacity from baseline at Week 1, 6, 12 post-injection with
associated with BOTOX for blepharospasm at the recommended dose                       up to two treatment cycles with BOTOX or placebo
(30 Units and below), strabismus, or for chronic migraine at the labeled                                     BOTOX                 BOTOX
doses have been reported.                                                                                                                               Placebo
                                                                                                            360 Units             240 Units
5.3 Injections In or Near Vulnerable Anatomic Structures                                                 ≥15%       ≥20%       ≥15%      ≥20%       ≥15%      ≥20%
Care should be taken when injecting in or near vulnerable anatomic
structures. Serious adverse events including fatal outcomes have been                  Week 1              4%        0%         3%         0%        7%         3%
reported in patients who had received BOTOX injected directly into salivary            Week 6              7%        4%         4%         2%        2%         2%
glands, the oro-lingual-pharyngeal region, esophagus and stomach. Some
patients had pre-existing dysphagia or significant debility. (Safety and               Week 12            10%        5%         2%         1%        4%         1%
effectiveness have not been established for indications pertaining to these           Differences from placebo were not statistically significant
injection sites.) Pneumothorax associated with injection procedure has been
reported following the administration of BOTOX near the thorax. Caution               In patients with reduced lung function, upper respiratory tract infections were
is warranted when injecting in proximity to the lung, particularly the apices.        also reported more frequently as adverse reactions in patients treated with
                                                                                      BOTOX than in patients treated with placebo [see Warnings and Precautions
5.4 Hypersensitivity Reactions                                                        (5.10)].
Serious and/or immediate hypersensitivity reactions have been reported.
                                                                                      In an ongoing double-blind, placebo-controlled, parallel group study in adult
These reactions include anaphylaxis, serum sickness, urticaria, soft tissue
                                                                                      patients with detrusor overactivity associated with a neurologic condition and
edema, and dyspnea. If such a reaction occurs, further injection of BOTOX
                                                                                      restrictive lung disease of neuromuscular etiology [defined as FVC 50-80%
should be discontinued and appropriate medical therapy immediately
                                                                                      of predicted value in patients with spinal cord injury between C5 and C8, or
instituted. One fatal case of anaphylaxis has been reported in which
                                                                                      MS] the event rate in change of Forced Vital Capacity ≥15% or ≥20% was
lidocaine was used as the diluent, and consequently the causal agent
                                                                                      generally greater in patients treated with BOTOX than in patients treated with
cannot be reliably determined.
                                                                                      placebo (see Table 5).
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