Professional Documents
Culture Documents
Very Low Real-Time Rate of Urinary Retention After
Very Low Real-Time Rate of Urinary Retention After
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
• 71% of patients with a neurologic condition stop taking at least one oral medication
within 12 months, according to a 5-year observational study3
• 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
2
Phase 3 Trials Study Design
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
0 2 12 52
Week 6:
Primary timepoint
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
-5
32%
-10
-9
36%
-15 -13
†
-20 66%
† 67%
* †
* P<.001 -21*
† P<.01 † P<.01 -22 †
-25
0 2 4 6 8 10 12 0 2 4 6 8 10 12
4
BOTOX® Delivered Long-lasting Response
60
40
20
0
0 90 180 270 360 450 0 100 200 300 400
5
BOTOX® Significantly Increased Cystometric Capacity
259.1 mL
+5% 271.2 mL 253.8 mL
+1% 256.6 mL
+12.1 mL +2.8 mL
+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<.001 * P<.001 Week 6
† Change from baseline represented by LS mean change based on an LOCF analysis using an ANCOVA model.
6
BOTOX® Significantly Reduced Detrusor Pressure
-10
6%
-20
* *
-28.1 -28.7
-30
45% 44%
* P<.001 * P<.001
-40
Mean baseline Mean baseline Mean baseline Mean baseline
63.1 cmH2O 57.4 cmH2O 65.6 cmH2O 43.7 cmH2O
† Change from baseline represented by LS mean change based on an LOCF analysis using an ANCOVA model.
7
Most Commonly Reported AEs and Patient CIC Usage
Most commonly reported adverse events (AEs) within the first 12 weeks4*†
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%)
* A 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
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
• 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
8
The BOTOX® Procedure Can Be Completed In-office
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
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 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
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
10
Coverage and Reimbursement
11
BOTOX
®
DELIVERS.
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*
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 • Upper 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
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)
Maximum Cystometric
Capacityb (mL)
N 123 129
Mean Baseline 253.8 259.1
Mean Change* at Week 6** 135.9 12.1 123.9 p<0.001
(89.1, 158.7)
BOTOX Placebo
Figure 6: Mean Change from Baseline in Number of Headache Days (N=64) (N=62)
for Study 2
Median Change from Baseline in Wrist
Flexor Muscle Tone on the Ashworth Scale†a -2.0* 0.0
†
Primary endpoint at Week 6
††
Secondary endpoints at Week 6
14.3 Upper Limb Spasticity * Significantly different from placebo (p≤0.05)
The efficacy and safety of BOTOX for the treatment of upper limb spasticity
a
BOTOX injected into both the flexor carpi radialis and ulnaris muscles
were evaluated in three randomized, multi-center, double-blind, placebo-
b
BOTOX injected into the flexor digitorum profundus and flexor digitorum
controlled studies. sublimis muscles
c
BOTOX injected into the adductor pollicis and flexor pollicis longus muscles
Study 1 included 126 patients (64 BOTOX and 62 placebo) with upper limb
spasticity (Ashworth score of at least 3 for wrist flexor tone and at least 2 Study 2 compared 3 doses of BOTOX with placebo and included 91 patients
for finger flexor tone) who were at least 6 months post-stroke. BOTOX (a total [BOTOX 360 Units (N=21), BOTOX 180 Units (N=23), BOTOX 90 Units
dose of 200 Units to 240 Units) and placebo were injected intramuscularly (N=21), and placebo (N=26)] with upper limb spasticity (expanded Ashworth
(IM) into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi score of at least 2 for elbow flexor tone and at least 3 for wrist flexor tone) who
radialis, flexor carpi ulnaris, and if necessary into the adductor pollicis and were at least 6 weeks post-stroke. BOTOX and placebo were injected with
flexor pollicis longus (see Table 14). Use of an EMG/nerve stimulator was EMG guidance into the flexor digitorum profundus, flexor digitorum sublimis,
recommended to assist in proper muscle localization for injection. Patients flexor carpi radialis, flexor carpi ulnaris, and biceps brachii (see Table 16).
were followed for 12 weeks.
Table 16: Study Medication Dose and Injection Sites in Study 2 Table 18: Primary and Key Secondary Endpoints by Muscle Group
and Study 3 and BOTOX Dose at Week 4 in Study 3
Total Dose BOTOX BOTOX BOTOX Placebo
BOTOX BOTOX BOTOX low dose mid dose high dose (N=19)
Volume Injection (90 Units) (180 Units) (360 Units)
low mid high
Muscles Injected (mL) Sites (N=23) (N=21) (N=22)
dose dose dose
per site (n)
(90 Units) (180 Units) (360 Units)
Median Change from
Wrist Baseline in Wrist Flexor
-1.0 -1.0 -1.5* -0.5
Flexor Carpi Ulnaris 10 Units 20 Units 40 Units 0.4 1 Muscle Tone on the
Ashworth Scale†b
Flexor Carpi Radialis 15 Units 30 Units 60 Units 0.6 1
Median Change from
Finger Baseline in Finger Flexor
-1.0 -1.0 -1.0* -0.5
Flexor Digitorum Muscle Tone on the
Profundus 7.5 Units 15 Units 30 Units 0.3 1 Ashworth Scale††c
on the HDSS 4 weeks after both of the first two treatment sessions or had
Splenius capitis/ a sustained response after their first treatment session and did not receive
83 38 25-50
cervicis re-treatment during the study.
Sternocleidomastoid 77 25 17-31 14.6 Blepharospasm
Botulinum toxin has been investigated for use in patients with blepharospasm
Levator scapulae 52 20 16-25 in several studies. In an open label, historically controlled study, 27 patients
with essential blepharospasm were injected with 2 Units of BOTOX at each
Trapezius 49 29 18-33 of six sites on each side. Twenty-five of the 27 patients treated with botulinum
toxin reported improvement within 48 hours. One patient was controlled with
Semispinalis 16 21 13-25 a higher dosage at 13 weeks post initial injection and one patient reported
mild improvement but remained functionally impaired.
Scalene 15 15 6-21 In another study, 12 patients with blepharospasm were evaluated in a
double-blind, placebo-controlled study. Patients receiving botulinum toxin
Longissimus 8 29 17-41 (n=8) improved compared with the placebo group (n=4). The effects of the
treatment lasted a mean of 12 weeks.
*The mid-range of dose is calculated as the 25th to 75th percentiles.
One thousand six hundred eighty-four patients with blepharospasm who were
There were several randomized studies conducted prior to the double-blind, evaluated in an open label trial showed clinical improvement as evaluated by
placebo-controlled study, which were supportive but not adequately designed measured eyelid force and clinically observed intensity of lid spasm, lasting an
to assess or quantitatively estimate the efficacy of BOTOX. average of 12 weeks prior to the need for re-treatment.
14.5 Primary Axillary Hyperhidrosis 14.7 Strabismus
The efficacy and safety of BOTOX for the treatment of primary axillary Six hundred seventy-seven patients with strabismus treated with one or more
hyperhidrosis were evaluated in two randomized, multi-center, double-blind, injections of BOTOX were evaluated in an open label trial. Fifty-five percent
placebo-controlled studies. Study 1 included adult patients with persistent of these patients improved to an alignment of 10 prism diopters or less when
primary axillary hyperhidrosis who scored 3 or 4 on a Hyperhidrosis Disease evaluated six months or more following injection.
Severity Scale (HDSS) and who produced at least 50 mg of sweat in each
axilla at rest over 5 minutes. HDSS is a 4-point scale with 1 = “underarm 16 HOW SUPPLIED/STORAGE AND HANDLING
sweating is never noticeable and never interferes with my daily activities”; BOTOX is supplied in a single-use vial in the following sizes:
to 4 = “underarm sweating is intolerable and always interferes with my 100 Units NDC 0023-1145-01
daily activities”. A total of 322 patients were randomized in a 1:1:1 ratio 200 Units NDC 0023-3921-02
to treatment in both axillae with either 50 Units of BOTOX, 75 Units of Vials of BOTOX have a holographic film on the vial label that contains the
BOTOX, or placebo. Patients were evaluated at 4-week intervals. Patients name “Allergan” within horizontal lines of rainbow color. In order to see the
who responded to the first injection were re-injected when they reported a hologram, rotate the vial back and forth between your fingers under a desk
re-increase in HDSS score to 3 or 4 and produced at least 50 mg sweat in lamp or fluorescent light source. (Note: the holographic film on the label is
each axilla by gravimetric measurement, but no sooner than 8 weeks after absent in the date/lot area.) If you do not see the lines of rainbow color or the
the initial injection. name “Allergan”, do not use the product and contact Allergan for additional
Study responders were defined as patients who showed at least a 2-grade information at 1-800-890-4345 from 7:00 AM to 3:00 PM Pacific Time.
improvement from baseline value on the HDSS 4 weeks after both of the first Storage
two treatment sessions or had a sustained response after their first treatment Unopened vials of BOTOX should be stored in a refrigerator (2° to 8°C) for
session and did not receive re-treatment during the study. Spontaneous up to 36 months for the 100 Units vial or up to 24 months for the 200 Units
resting axillary sweat production was assessed by weighing a filter paper held vial. Do not use after the expiration date on the vial. Administer BOTOX within
in the axilla over a period of 5 minutes (gravimetric measurement). Sweat 24 hours of reconstitution; during this period reconstituted BOTOX should
production responders were those patients who demonstrated a reduction in be stored in a refrigerator (2° to 8°C). Reconstituted BOTOX should be clear,
axillary sweating from baseline of at least 50% at week 4. colorless, and free of particulate matter.
In the three study groups the percentage of patients with baseline HDSS 17 PATIENT COUNSELING INFORMATION
score of 3 ranged from 50% to 54% and from 46% to 50% for a score of “See FDA-approved patient labeling (Medication Guide)”
4. The median amount of sweat production (averaged for each axilla) was
102 mg, 123 mg, and 114 mg for the placebo, 50 Units and 75 Units Provide a copy of the Medication Guide and review the contents with
groups respectively. the patient.
17.1 Swallowing, Speaking or Breathing Difficulties, or Other 2. Spread of toxin effects. In some cases, the effect of
Unusual Symptoms botulinum toxin may affect areas of the body away from the
Patients should be advised to inform their doctor or pharmacist if they
develop any unusual symptoms (including difficulty with swallowing, injection site and cause symptoms of a serious condition
speaking, or breathing), or if any existing symptom worsens [see Boxed called botulism. The symptoms of botulism include:
Warning and Warnings and Precautions (5.2, 5.5)].
• loss of strength and muscle weakness all over the body
17.2 Ability to Operate Machinery or Vehicles
Patients should be counseled that if loss of strength, muscle weakness, • double vision
blurred vision, or drooping eyelids occur, they should avoid driving a car
or engaging in other potentially hazardous activities. • blurred vision and drooping eyelids
17.3 Voiding Difficulties after Bladder Injections
After bladder injections for urinary incontinence, patients should be • hoarseness or change or loss of voice (dysphonia)
instructed to contact their physician if they experience difficulties in voiding.
• trouble saying words clearly (dysarthria)
Manufactured by: Allergan Pharmaceuticals Ireland
a subsidiary of: Allergan, Inc. • loss of bladder control
2525 Dupont Dr.
Irvine, CA 92612 • trouble breathing
© 2012 Allergan, Inc.
• trouble swallowing
®
mark owned by Allergan, Inc.
U.S. Patents 5,437,291; 5,714,468; 6,667,041; 6,683,049; 6,896,886; These symptoms can happen hours, days, to weeks after you
6,974,578; 7,001,602; 7,429,387; and 7,449,192
receive an injection of BOTOX or BOTOX Cosmetic.
These problems could make it unsafe for you to drive a car or
do other dangerous activities. See “What should I avoid while
Based on 72309US11C and 72312US11C receiving BOTOX or BOTOX Cosmetic?”
MEDICATION GUIDE There has not been a confirmed serious case of spread of
BOTOX® toxin effect away from the injection site when BOTOX has been
used at the recommended dose to treat chronic migraine, severe
BOTOX® Cosmetic
underarm sweating, blepharospasm, or strabismus, or when
(Boe-tox)
BOTOX Cosmetic has been used at the recommended dose
(onabotulinumtoxinA)
to treat frown lines.
for Injection
Read the Medication Guide that comes with BOTOX or What are BOTOX and BOTOX Cosmetic?
BOTOX Cosmetic before you start using it and each time it is
given to you. There may be new information. This information BOTOX is a prescription medicine that is injected into muscles
does not take the place of talking with your doctor about your and used:
medical condition or your treatment. You should share this • to treat leakage of urine (incontinence) in adults with
information with your family members and caregivers. overactive bladder due to neurologic disease.
What is the most important information I should know • to prevent headaches in adults with chronic migraine who
about BOTOX and BOTOX Cosmetic? have 15 or more days each month with headache lasting
BOTOX and BOTOX Cosmetic may cause serious side 4 or more hours each day.
effects that can be life threatening, including: • to treat increased muscle stiffness in elbow, wrist, and
• Problems breathing or swallowing finger muscles in adults with upper limb spasticity.
• Spread of toxin effects • to treat the abnormal head position and neck pain that
happens with cervical dystonia (CD) in adults.
These problems can happen hours, days, to weeks after an
injection of BOTOX or BOTOX Cosmetic. Call your doctor • to treat certain types of eye muscle problems (strabismus)
or get medical help right away if you have any of these or abnormal spasm of the eyelids (blepharospasm) in
problems after treatment with BOTOX or BOTOX Cosmetic: people 12 years and older.
1. P
roblems swallowing, speaking, or breathing. These BOTOX is also injected into the skin to treat the symptoms
problems can happen hours, days, to weeks after an of severe underarm sweating (severe primary axillary
injection of BOTOX or BOTOX Cosmetic usually because hyperhidrosis) when medicines used on the skin (topical)
the muscles that you use to breathe and swallow can do not work well enough.
become weak after the injection. Death can happen as a BOTOX Cosmetic is a prescription medicine that is injected
complication if you have severe problems with swallowing or into muscles and used to improve the look of moderate to
breathing after treatment with BOTOX or BOTOX Cosmetic. severe frown lines between the eyebrows (glabellar lines) in
• People with certain breathing problems may need to use adults younger than 65 years of age for a short period of
muscles in their neck to help them breathe. These people time (temporary).
may be at greater risk for serious breathing problems with It is not known whether BOTOX is safe or effective in people
BOTOX or BOTOX Cosmetic. younger than:
• Swallowing problems may last for several months. People • 18 years of age for treatment of urinary incontinence
who cannot swallow well may need a feeding tube to
receive food and water. If swallowing problems are severe, • 18 years of age for treatment of chronic migraine
food or liquids may go into your lungs. People who already • 18 years of age for treatment of spasticity
have swallowing or breathing problems before receiving
BOTOX or BOTOX Cosmetic have the highest risk of
getting these problems.
• 16 years of age for treatment of cervical dystonia • h
ave problems emptying your bladder on your own and
are being treated for urinary incontinence
• 18 years of age for treatment of hyperhidrosis
• a
re pregnant or plan to become pregnant. It is not known
• 12 years of age for treatment of strabismus if BOTOX or BOTOX Cosmetic can harm your
or blepharospasm unborn baby.
BOTOX Cosmetic is not recommended for use in children • a
re breast-feeding or plan to breastfeed. It is not known
younger than 18 years of age. if BOTOX or BOTOX Cosmetic passes into breast milk.
It is not known whether BOTOX and BOTOX Cosmetic Tell your doctor about all the medicines you take, including
are safe or effective to prevent headaches in people with prescription and nonprescription medicines, vitamins and
migraine who have 14 or fewer headache days each month herbal products. Using BOTOX or BOTOX Cosmetic with
(episodic migraine). certain other medicines may cause serious side effects. Do
It is not known whether BOTOX and BOTOX Cosmetic are not start any new medicines until you have told your
safe or effective for other types of muscle spasms or for severe doctor that you have received BOTOX or BOTOX Cosmetic
sweating anywhere other than your armpits. in the past.
Who should not take BOTOX or BOTOX Cosmetic? Especially tell your doctor if you:
Do not take BOTOX or BOTOX Cosmetic if you: • have received any other botulinum toxin product in the
• are allergic to any of the ingredients in BOTOX or last four months
BOTOX Cosmetic. See the end of this Medication Guide • have received injections of botulinum toxin, such
for a list of ingredients in BOTOX and BOTOX Cosmetic. as Myobloc® (rimabotulinumtoxinB), Dysport ®
• h
ad an allergic reaction to any other botulinum toxin (abobotulinumtoxinA), or Xeomin® (incobotulinumtoxinA)
product such as Myobloc®, Dysport ®, or Xeomin® in the past. Be sure your doctor knows exactly which
product you received.
• have a skin infection at the planned injection site
• have recently received an antibiotic by injection
• a
re being treated for urinary incontinence and have
a urinary tract infection (UTI) • take muscle relaxants
• are being treated for urinary incontinence and find that • take an allergy or cold medicine
you cannot empty your bladder on your own (only applies • take a sleep medicine
to people who are not routinely catheterizing)
• take anti-platelets (aspirin-like products) and/or anti-
What should I tell my doctor before taking BOTOX coagulants (blood thinners)
or BOTOX Cosmetic?
Ask your doctor if you are not sure if your medicine is
Tell your doctor about all your medical conditions, one that is listed above.
including if you:
Know the medicines you take. Keep a list of your medicines
• h
ave a disease that affects your muscles and nerves (such with you to show your doctor and pharmacist each time you
as amyotrophic lateral sclerosis [ALS or Lou Gehrig’s get a new medicine.
disease], myasthenia gravis or Lambert-Eaton syndrome).
See “What is the most important information I should know How should I take BOTOX or BOTOX Cosmetic?
about BOTOX and BOTOX Cosmetic?”
• BOTOX or BOTOX Cosmetic is an injection that your
• have allergies to any botulinum toxin product doctor will give you.
• h
ad any side effect from any botulinum toxin product • BOTOX is injected into your affected muscles, skin,
in the past or bladder.
• h
ave or have had a breathing problem, such as asthma • BOTOX Cosmetic is injected into your affected muscles.
or emphysema
our doctor may change your dose of BOTOX or
• Y
• have or have had swallowing problems BOTOX Cosmetic, until you and your doctor find the
best dose for you.
• have or have had bleeding problems
• Your doctor will tell you how often you will receive
• have plans to have surgery your dose of BOTOX or BOTOX Cosmetic injections.
• had surgery on your face What should I avoid while taking BOTOX or
• h
ave weakness of your forehead muscles, such as trouble BOTOX Cosmetic?
raising your eyebrows BOTOX and BOTOX Cosmetic may cause loss of strength
• have drooping eyelids or general muscle weakness, or vision problems within
hours to weeks of taking BOTOX or BOTOX Cosmetic. If
• have any other change in the way your face normally looks this happens, do not drive a car, operate machinery,
or do other dangerous activities. See “What is the most
• h
ave symptoms of a urinary tract infection (UTI) and are
important information I should know about BOTOX and
being treated for urinary incontinence. Symptoms of a
BOTOX Cosmetic?”
urinary tract infection may include pain or burning with
urination, frequent urination, or fever.
What are the possible side effects of BOTOX and Issued: 08/2011
BOTOX Cosmetic?
This Medication Guide has been approved by the U.S. Food
BOTOX and BOTOX Cosmetic can cause serious side and Drug Administration.
effects. See “What is the most important information I should
know about BOTOX and BOTOX Cosmetic?” Manufactured by: Allergan Pharmaceuticals Ireland
a subsidiary of: Allergan, Inc.
Other side effects of BOTOX and BOTOX Cosmetic include: 2525 Dupont Dr.
Irvine, CA 92612
• dry mouth
© 2012 Allergan, Inc.
• discomfort or pain at the injection site
®
mark owned by Allergan, Inc.
• tiredness U.S. Patents 5,437,291; 5,714,468; 6,667,041; 6,683,049;
• headache 6,896,886; 6,974,578; 7,001,602; 7,429,387; and 7,449,192
• neck pain Myobloc® is a registered trademark of Solstice
Neurosciences, Inc.
• e
ye problems: double vision, blurred vision, decreased Dysport ® is a registered trademark of Ipsen Biopharm
eyesight, drooping eyelids, swelling of your eyelids, and Limited Company.
dry eyes. Xeomin® is a registered trademark of Merz Pharma GmbH
• urinary tract infection in people being treated for & Co KGaA.
urinary incontinence
• inability to empty your bladder on your own and are
being treated for urinary incontinence.
Based on 72309US11C and 72312US11C
• allergic reactions. Symptoms of an allergic reaction to 72284US13C
BOTOX or BOTOX Cosmetic may include: itching, rash, red
itchy welts, wheezing, asthma symptoms, or dizziness or
feeling faint. Tell your doctor or get medical help right away
if you are wheezing or have asthma symptoms, or if you
become dizzy or faint.
Tell your doctor if you have any side effect that bothers you
or that does not go away.
These are not all the possible side effects of BOTOX and
BOTOX Cosmetic. For more information, ask your doctor
or pharmacist.
Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.
General information about BOTOX and BOTOX Cosmetic:
Medicines are sometimes prescribed for purposes other than
those listed in a Medication Guide.
This Medication Guide summarizes the most important
information about BOTOX and BOTOX Cosmetic. If you
would like more information, talk with your doctor. You can ask
your doctor or pharmacist for information about BOTOX and
BOTOX Cosmetic that is written for healthcare professionals.
For more information about BOTOX and BOTOX Cosmetic
call Allergan at 1-800-433-8871 or go to www.BOTOX.com.
What are the ingredients in BOTOX and
BOTOX Cosmetic?
Active ingredient: botulinum toxin type A
Inactive ingredients: human albumin and sodium chloride
APC40NF12