Injection Workbook for Chronic Migraine

Guidance for identifying BOTOX® patients,

the injection procedure, and setting up your practice

Indication
Chronic Migraine
BOTOX® for injection is indicated for the prophylaxis of headaches in adult patients with chronic
migraine (≥ 15 days per month with headache lasting 4 hours a day or longer).
Important Limitations
Safety and effectiveness have not been established for the prophylaxis of episodic migraine
(14 headache days or fewer per month) in 7 placebo-controlled studies.
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING

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 upper limb spasticity and at lower doses.

Please see additional Important Safety Information about BOTOX® on following pages.
 Introduction Table
Notes
of contents
page to come
This workbook is designed to help you learn and apply the proven BOTOX® Injection Paradigm. It LEARN ABOUT THE PATIENT
also contains information to help injectors identify appropriate BOTOX® candidates, understand
procedure-related anatomy, manage patient expectations, and integrate the procedure into Identifying BOTOX® candidates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
the practice.
LEARN ABOUT THE PROCEDURE
Reference material accompanying this workbook: PREEMPT* injection protocol overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
General injection considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Reconstitution pocket guide
Anterior injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
— Anatomy of the face and head . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
— Corrugator injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
— Procerus injection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
— Frontalis injections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
— Temporalis injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Posterior injections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
— Anatomy of the neck and head . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
— Occipitalis injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
— Cervical paraspinal injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
— Trapezius injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Patient assessment before injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Managing patient expectations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

LEARN ABOUT SETTING UP THE PRACTICE

Tips to adopt BOTOX® in the office. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Resources available to patients and injectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
IMPORTANT SAFETY INFORMATION (continued) Helpful phone numbers and websites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
CONTRAINDICATIONS
*PREEMPT = Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy.
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. IMPORTANT SAFETY INFORMATION (continued)
WARNINGS AND PRECAUTIONS (continued)
WARNINGS AND PRECAUTIONS
Serious Adverse Reactions With Unapproved Use
Lack of Interchangeability Between Botulinum Toxin Products
Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with
The potency Units of BOTOX® are specific to the preparation and assay method utilized. They
some adverse reactions associated with fatal outcomes, have been reported in patients who received
are not interchangeable with other preparations of botulinum toxin products and, therefore,
BOTOX® injections for unapproved uses. In these cases, the adverse reactions were not necessarily related
Units of biological activity of BOTOX® cannot be compared to nor converted into Units of any
to distant spread of toxin, but may have resulted from the administration of BOTOX® to the site of injection
other botulinum toxin products assessed with any other specific assay method.
and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant
Spread of Toxin Effect disabilities. There is insufficient information to identify factors associated with an increased risk for adverse
See Boxed Warning. reactions associated with the unapproved uses of BOTOX®. The safety and effectiveness of BOTOX® for
No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX® for unapproved
Please see usesImportant
have not been
Safetyestablished.
Information including Boxed Warning about BOTOX®
2 chronic migraine at the labeled dose have been reported. Please see additional
throughout Important Safety Information about BOTOX® on following pages.
this brochure. 3 43
 Identifying BOTOX® candidates Considerations when evaluating treatment plans

Practical clinical criteria for Chronic Migraine diagnosis1,2 Prevention may be an important part of a Chronic Migraine management plan. Aside from ensuring
adequate prevention, a management plan may include optimizing acute medication use/limiting
medication overuse, addressing comorbid conditions, and adjusting patient lifestyles (eg, diet, exercise,

15 curbing caffeine overuse).3,4

+
or more headache Treatment planning begins with a thorough history, which can include inquiry around these topics:
days per month Headaches last

4
8
hours or more per day

or more headache Is the patient Is the patient Is the patient Has the patient Are there
days are migraine days using more acute responding meeting followed the contraindications
medications than appropriately treatment prescribed to some
recommended? to acute goals? preventive treatment
medications? regimen? options?
• With or without medication overuse2

Focus on headache days vs migraine attacks

Revisit appropriate Chronic Migraine patients’
• Not all days need to be associated with migraine2 treatment plans with BOTOX® in mind
• Days when headaches were successfully treated with migraine-specific acute medications
(eg, triptans) are also considered headache days2 A history of preventive use5

• Ask about headache-free days if patient cannot recall number of actual headache days
Chronic Migraine patients
have tried

3.9
preventive treatments
on average (n = 493)5

IMPORTANT SAFETY INFORMATION (continued)

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued)
WARNINGS AND PRECAUTIONS (continued) Pre-Existing Neuromuscular Disorders
Hypersensitivity Reactions Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular
Serious and/or immediate hypersensitivity reactions have been reported. These reactions include junction disorders (eg, myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given
anaphylaxis, serum sickness, urticaria, soft-tissue edema, and dyspnea. If such a reaction occurs, further botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant
injection of BOTOX® should be discontinued and appropriate medical therapy immediately instituted. One effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia,
fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently and respiratory compromise from therapeutic doses of BOTOX® (see Adverse Reactions).
4 the causal agent cannot be reliably determined. Please see additional Important Safety Information about BOTOX® on following pages. 5
 Identifying BOTOX® candidates (continued)
As part of the evaluation, documenting symptoms for a Chronic Migraine diagnosis is important.
! ! !
PREEMPT injection protocol overview
PREEMPT injection protocol is based on 10 years of study to assess patient type, muscle
When patients can understand the symptoms of their condition, they may feel less frustrated and selection, dose, and treatment interval.8-16
more open to treatment options.

Headache frequency
and duration
Evaluate both headache days and
headache-free days 155 15512
15512 311231 31
UNITS UNITSWEEKS
UNITS
WEEKSSITES
WEEKS
SITES SITES
Headache severity Ask about symptoms and intensity, which may
shed light on headache severity 6 PROVEN DOSE PROVEN SCHEDULE PROVEN SITES
155 Units1 Re-treatment 31 sites across
every 12 weeks1 7 specific head and
Headache impact Uncover how headache affects daily activities
to avoid a patient minimizing symptoms6 neck muscle areas1
Summary of dose by area1

MUSCLE AREA RECOMMENDED DOSE/NUMBER OF SITES

Greater disability correlates with headache frequency 7

Corrugator 10 Units divided between 2 sites

Procerus 5 Units in 1 site

Patients with Chronic Migraine are significantly more likely to be severely disabled than those
with episodic migraine (64.3% vs 43.2% Migraine Disability Assessment [MIDAS] grade IV). Frontalis 20 Units divided between 4 sites

Temporalis 40 Units divided between 8 sites

Occipitalis 30 Units divided between 6 sites

Cervical paraspinal 20 Units divided between 4 sites

Trapezius 30 Units divided between 6 sites

TOTAL DOSE 155 Units* divided between 31 sites

*Document and discard the 45-Unit wastage.

The following section provides a step-by-step overview of the injection paradigm for BOTOX®.
Departures from the approved paradigm may lead to efficacy results and adverse events different from
those seen in the clinical trials.

IMPORTANT SAFETY INFORMATION (continued) IMPORTANT SAFETY INFORMATION (continued)

WARNINGS AND PRECAUTIONS (continued) WARNINGS AND PRECAUTIONS (continued)
Dysphagia and Breathing Difficulties Human Albumin and Transmission of Viral Diseases
Treatment with BOTOX® and other botulinum toxin products can result in swallowing or breathing This product contains albumin, a derivative of human blood. Based on effective donor screening and
difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases.
these complications. In most cases, this is a consequence of weakening of muscles in the area of A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely
injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.
6 (see Boxed Warning). Please see additional Important Safety Information about BOTOX® on following pages. 7
 General injection considerations DURING INJECTION
• Inject on 1 side first for bilateral injections, then proceed to the other side and repeat at all the
STANDARD METHODS REGARDLESS OF AREA specified sites
• For each injection, the injection volume will be 0.1 mL (equivalent to 5 Units)1
• Consider changing needles frequently to reduce patient discomfort; consider using 1 needle per
• Consider injecting in the most superficial aspect of the muscle area or changing every 4 to 6 sites

• Evaluate the anatomy, including relevant function and the effects of treatment on these muscles • Inject with the bevel up, pointing away from the skin
(eg, weakening)
• It may be helpful to hold the hub of the needle with 1 hand to ensure the needle does not twist
• Recognize unique anatomy, as no 2 patients are alike; focus on the muscle, not measurements, to
– Push the plunger with the other hand to administer the medication
adjust for individual anatomical variations
• Aspirate to ensure no blood return
• Consider location, depth, and angle carefully, as the site of medication delivery may be different
from the needle insertion point • Target the muscle—The needle should be inserted through the epidermis/dermis layer, which
– Injection sites depicted in diagrams represent delivery point of the medication may feel more rigid when penetrated. The injection should be given just when there is a decrease
in resistance, avoiding the periosteum. This decrease in resistance may be subdermal,
not intramuscular
BEFORE INJECTION
• Examine the patient to identify unique anatomy and any muscle weakness or pain/tenderness
– Visually inspect the muscle
– Ask the patient to activate the muscle
– Palpate the muscle

• Verify the needle is securely fastened to the injection syringe

• Line up the bevel of the needle with the gradations on the syringe so the bevel is facing upward;
this will help you more easily orient the bevel of the needle when injecting
Example of procerus
injection. Note the angle used
Figure 1* to avoid the periosteum and
target the muscle (Figure 1).†

IMPORTANT SAFETY INFORMATION (continued)

*This is a hypothetical patient.
ADVERSE REACTIONS †
Muscles and anatomical structures shown for anatomical reference only.
The following adverse reactions to BOTOX® for injection are discussed in greater detail in the
following sections: Spread of Toxin Effect (see Boxed Warning); Hypersensitivity Reactions (see
Contraindications and Warnings and Precautions); Dysphagia and Breathing Difficulties (see Warnings
and Precautions).
Chronic Migraine IMPORTANT SAFETY INFORMATION (continued)
The most frequently reported adverse reactions following injection of BOTOX® for chronic migraine vs ADVERSE REACTIONS (continued)
placebo include, respectively: neck pain (9% vs 3%), headache (5% vs 3%), eyelid ptosis (4% vs < 1%), Post Marketing Experience
migraine (4% vs 3%), muscular weakness (4% vs < 1%), musculoskeletal stiffness (4% vs 1%), bronchitis There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia,
(3% vs 2%), injection-site pain (3% vs 2%), musculoskeletal pain (3% vs 1%), myalgia (3% vs 1%), facial and/or other significant debility or anaphylaxis, after treatment with botulinum toxin. There have also
paresis (2% vs 0%), hypertension (2% vs 1%), and muscle spasms (2% vs 1%). been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial
Severe worsening of migraine requiring hospitalization occurred in approximately 1% of BOTOX® treated infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular
patients in study 1 and study 2, usually within the first week after treatment, compared with 0.3% of disease. The exact relationship of these events to the botulinum toxin injection has not been established.
8 placebo-treated patients. Please see additional Important Safety Information about BOTOX® on following pages. 9
 Anterior injections*
Anatomy of the face and head
This section will highlight muscle area anatomy to provide additional context for the anterior Temporalis
injection sites. Originates from the temporal fossa
and deep layer of the temporal
fascia, and inserts into the top and
Frontalis medial surface of the coronoid
Originates from the epicranial process of the mandible.17
aponeurosis, and attaches distally
to the skin of the forehead
and eyebrow.17

Corrugator
Attaches to the nasal-frontal bone
medially and the skin of the
eyebrow laterally.17,18

Procerus
Originates from the aponeurotic Interrelationship between muscles
fascia of the nose and inserts into • Corrugator muscle fibers and frontalis muscle fibers interdigitate in the region of the medial brow
the glabellar skin.17 where the corrugator inserts into skin
• On the corrugator’s medial aspect, it is deep to both the procerus muscle and the superficial,
thinned-out frontalis muscle fibers
*Muscles and anatomical structures shown for anatomical reference only.

Because of the close proximity of these muscles, pay close attention to the depth and angle
of the needle. There can be a difference between the insertion point and where the medication
is ultimately delivered.

IMPORTANT SAFETY INFORMATION (continued)

DRUG INTERACTIONS
Co-administration of BOTOX® and aminoglycosides or other agents interfering with neuromuscular
transmission (eg, curare-like compounds) should only be performed with caution as the effect of the Indication
toxin may be potentiated. Use of anticholinergic drugs after administration of BOTOX® may potentiate Chronic Migraine
systemic anticholinergic effects. The effect of administering different botulinum neurotoxin products at BOTOX® for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine
the same time or within several months of each other is unknown. Excessive neuromuscular weakness (≥ 15 days per month with headache lasting 4 hours a day or longer).
may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a Important Limitations
previously administered botulinum toxin. Excessive weakness may also be exaggerated by administration Safety and effectiveness have not been established for the prophylaxis of episodic migraine
of a muscle relaxant before or after administration of BOTOX®. (14 headache days or fewer per month) in 7 placebo-controlled studies.
Please see accompanying full Prescribing Information including Boxed Warning and Please see Important Safety Information including Boxed Warning about BOTOX®
10 Medication Guide. on following pages. 11
 Anterior injections (continued)* Functional anatomy (continued)

Functional anatomy The procerus muscle draws

This section will highlight the functional anatomy of each anterior injection site, which may be important down the medial aspect of
to consider when injecting. the brow.17

The frontalis muscle is a brow Activating the procerus creates a

elevator, pulling the brow upward.17 transverse ridge over the nose
Weakening of this muscle may Figure 4†
(Figure 4).17
result in brow ptosis.

The temporalis is a masticatory

Activating the frontalis creates muscle. Clenching the teeth
transverse lines on the forehead activates the temporalis and can
(Figure 2).17 help localize the muscle (Figure 5).17
Figure 2

The corrugator muscle is a

brow depressor, pulling the brow
downward.17 Weakening of this
muscle may elevate the brow.

Figure 5
Activating the corrugator creates †
This is a hypothetical patient.
vertical lines between the brow
(Figure 3).17

Figure 3

IMPORTANT SAFETY INFORMATION (continued)

*Muscles and anatomical structures shown for anatomical reference only.
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
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING the formulation.
WARNINGS AND PRECAUTIONS
WARNING: DISTANT SPREAD OF TOXIN EFFECT
Lack of Interchangeability Between Botulinum Toxin Products
Postmarketing reports indicate that the effects of BOTOX® and all botulinum toxin products The potency Units of BOTOX® are specific to the preparation and assay method utilized. They
may spread from the area of injection to produce symptoms consistent with botulinum toxin
are not interchangeable with other preparations of botulinum toxin products and, therefore,
effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia,
dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have Units of biological activity of BOTOX® cannot be compared to nor converted into Units of any
been reported hours to weeks after injection. Swallowing and breathing difficulties can be life other botulinum toxin products assessed with any other specific assay method.
threatening, and there have been reports of death. The risk of symptoms is probably greatest Spread of Toxin Effect
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 See Boxed Warning.
predispose them to these symptoms. In unapproved uses, including spasticity in children, and No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX® for
in approved indications, cases of spread of effect have been reported at doses comparable to chronic migraine at the labeled dose have been reported.
those used to treat cervical dystonia and upper limb spasticity and at lower doses.
12 Please see additional Important Safety Information about BOTOX® on following pages. 13
 Standard corrugator PREEMPT protocol*
Dose1
• 5 Units (0.1 mL) in each site
• Total of 10 Units divided into
2 sites

Corrugator muscle17,* Medial inferior edge

of the superior orbital rim17,*

Injection site A
• About 1.5 cm (≈ 1 fingerbreadth)
above the medial inferior edge Figure 6
of the superior orbital rim (bony A A
landmark). This may vary based
on individual anatomy Additional factors to consider prior to injection
• Ask the patient to furrow the brow, which activates the corrugator and causes medial and inferior
movement of the brow
• Palpate and pinch the muscle, holding between the thumb and index finger (Figure 6)
• Consider injecting at a 90º angle into the belly of the muscle, remaining above the periosteum, to help
Corrugator injection sites1 ensure medication delivery into the corrugator and not into a nearby muscle (Figure 6)
• Because facial anatomy is different, the standard measurements for some patients may lead to
*Muscles and anatomical structures shown for anatomical reference only. inadvertent penetration of the frontalis muscle, which may lead to brow ptosis
• Corrugator muscles are thin, so injecting too deep can hit the periosteum and may trigger
headache/migraine
IMPORTANT SAFETY INFORMATION (continued) • Injecting with the needle pointed upward and laterally at a 45º angle may increase the risk of
WARNINGS AND PRECAUTIONS (continued) frontalis penetration
Serious Adverse Reactions With Unapproved Use
Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with Note: The considerations above cannot eliminate the risk of adverse events following BOTOX® injections.
some adverse reactions associated with fatal outcomes, have been reported in patients who received
BOTOX® injections for unapproved uses. In these cases, the adverse reactions were not necessarily related
to distant spread of toxin, but may have resulted from the administration of BOTOX® to the site of injection
and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant
disabilities. There is insufficient information to identify factors associated with an increased risk for adverse
reactions associated with the unapproved uses of BOTOX®. The safety and effectiveness of BOTOX® for
unapproved uses have not been established.
14 Please see additional Important Safety Information about BOTOX® on following pages. 15
 Standard procerus PREEMPT protocol*
Dose1
• 5 Units (0.1 mL) in 1 site
• Total of 5 Units

Procerus muscle17,* Medial inferior edge

of the superior orbital rim17,*

Injection site B
• The base of the procerus resides
approximately midway between
the 2 corrugator injections B Figure 7

Additional factors to consider prior to injection

• Ask the patient to furrow the brow; use the vertical and horizontal lines as orientation sites
• Inject into the belly of the muscle at 90º to deliver medication into the procerus and not a nearby
muscle (eg, frontalis) (Figure 7)
• The procerus muscle is thin, so injecting too deep can hit the periosteum
Procerus injection site1
• Injecting too high in the brow area, in the lower frontalis instead of the procerus, can lead to
*Muscles and anatomical structures shown for anatomical reference only.
brow ptosis
IMPORTANT SAFETY INFORMATION (continued)
WARNINGS AND PRECAUTIONS (continued) Be cautious of the thin muscles of the forehead and brow. Stay in the most superficial aspect
Hypersensitivity Reactions of the muscle to avoid hitting the periosteum.
Serious and/or immediate hypersensitivity reactions have been reported. These reactions include
anaphylaxis, serum sickness, urticaria, soft-tissue edema, and dyspnea. If such a reaction occurs, further Note: The considerations above cannot eliminate the risk of adverse events following BOTOX® injections.
injection of BOTOX® should be discontinued and appropriate medical therapy immediately instituted. One
fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently IMPORTANT SAFETY INFORMATION (continued)
the causal agent cannot be reliably determined. WARNINGS AND PRECAUTIONS (continued)
Pre-Existing Neuromuscular Disorders Dysphagia and Breathing Difficulties
Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular Treatment with BOTOX® and other botulinum toxin products can result in swallowing or breathing
junction disorders (eg, myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to
botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant these complications. In most cases, this is a consequence of weakening of muscles in the area of
effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia, injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing
and respiratory compromise from therapeutic doses of BOTOX® (see Adverse Reactions). (see Boxed Warning).
16 Please see additional Important Safety Information about BOTOX® on following pages. Please see additional Important Safety Information about BOTOX® on following pages. 17
 Standard frontalis PREEMPT protocol*
Dose1
Frontalis muscles17,*
• 5 Units (0.1 mL) in each site
• Total 20 Units divided into 4 sites

Medial injection site C1

• Visually, draw a vertical line
up from the medial inferior edge
of the superior orbital rim

• Medial injection is generally

within the upper one-third of the
forehead, and at least 1.5 cm
(≈ 1 fingerbreadth) above the
corrugator injection site. This Medial inferior edge
may vary based on individual of the superior orbital rim17,*
anatomy

Figure 9

C2
C2 C1 C1 C2 Additional factors to consider prior to injection
• Angle the needle superiorly at 45º (Figure 9)
• Frontalis muscles are thin, so inject in the most superficial aspect of the muscle to avoid
the periosteum
• Injecting in the frontalis too low may cause medial brow weakness and lateral brow elevation; the
elevation occurs as a compensatory mechanism to keep the eyelids open in the presence of medial
brow weakness
Frontalis injection sites1 • Weakening the frontalis may exacerbate preexisting brow ptosis; counsel patients with this condition
accordingly (see page 32)
• Consider that injection points are different than medication delivery points
Lateral injection site C2 Second frontalis First frontalis • If patients are concerned about discomfort, the injector may consider a topical anesthetic in this area
• Lateral injections are parallel, injection injection
≈ 1.5 cm
lining up with the lateral limbus of Account for individual anatomy. Forehead sizes are different, so generally stay within the
the cornea, and at least 1.5 cm upper one-third of the forehead.
(≈ 1 fingerbreadth) lateral to the
medial injection site (Figure 8). Note: The considerations above cannot eliminate the risk of adverse events following BOTOX® injections.
This may vary based on
individual anatomy IMPORTANT SAFETY INFORMATION (continued)
WARNINGS AND PRECAUTIONS (continued)
Figure 8† Human Albumin and Transmission of Viral Diseases
This product contains albumin, a derivative of human blood. Based on effective donor screening and
Lateral limbus of the cornea17,* product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases.
18 Please see additional Important Safety Information about BOTOX® on following pages. 19
*Muscles and anatomical structures shown for anatomical reference only.
†
This is a hypothetical patient.
 Standard temporalis PREEMPT protocol*
Dose1
• 5 Units (0.1 mL) in each site
• Total 40 Units divided into 8 sites
(4 on each side of head)

Injection site 1D1

• Find the tragus of the ear and
move your finger vertically up the
side of the head about 3 cm
(≈ 2 fingerbreadths)

Injection site 1
D2
• Move about 1.5 cm to 3 cm
(≈ 1-2 fingerbreadths) up from the
first injection, still in line with the Temporalis muscle17,* Tragus of the ear17,* Superior helix19,*
tragus of the ear
Figure 10

Injection site 1
D3 Additional factors to consider prior to injection
• Move about 1.5 cm to 3 cm • Inject the most superficial aspect of the muscle at 45º (Figure 10)
(≈ 1-2 fingerbreadths) forward, D2 D4
• Aspirate to ensure no blood return
toward the face, from the first
and second injections. Make the D3 • Keep injections within the hairline, particularly for the most anterior injection site; the needle should
third injection halfway vertically be angled posteriorly (Figure 10)
between injection sites 1 and 2 D1
• Clenching the teeth activates the temporalis and can help localize the muscle
• Area may be prone to bleeding. Apply pressure immediately and manage before the patient leaves
• A finger can be placed on the middle of the helix of the ear to guide the fourth injection
Injection site 1
D4
• There are fibrous bands within the temporalis muscle, and patients may hear the injection needle
• Move about 1.5 cm (≈ 1
fingerbreadth) back from the passing through this region
second injection, and in line with Note: The considerations above cannot eliminate the risk of adverse events following BOTOX® injections.
the midportion (helix) of the ear

Temporalis injection sites1

IMPORTANT SAFETY INFORMATION (continued)
*Muscles and anatomical structures shown for anatomical reference only. ADVERSE REACTIONS
IMPORTANT SAFETY INFORMATION (continued) The following adverse reactions to BOTOX® for injection are discussed in greater detail in the
WARNINGS AND PRECAUTIONS (continued) following sections: Spread of Toxin Effect (see Boxed Warning); Hypersensitivity Reactions (see
Human Albumin and Transmission of Viral Diseases (continued) Contraindications and Warnings and Precautions); Dysphagia and Breathing Difficulties (see Warnings
A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely and Precautions).
20 remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin. Please see additional Important Safety Information about BOTOX® on following pages. 21
 Posterior injections* Functional anatomy

Muscles of the neck and posterior head

This section will highlight muscle area and functional anatomy for each posterior injection site, which
may be important to consider when injecting.

Occipitalis—Originates at the
highest nuchal line and inserts into
the epicranial aponeurosis, which
is attached to the frontalis.17

Cervical paraspinal muscles

should be considered a group
(including the splenius capitis and
semispinalis capitis) running deep
alongside the cervical spine.17

Trapezius—A flat, triangular

muscle situated over the back of
the neck and upper thorax.17
Figure 11 Figure 12†
*Muscles and anatomical structures shown for anatomical reference only.
One function of the occipitalis is as an anchor for the frontalis.17

Cervical paraspinal muscles stabilize and allow for movement of the head and cervical spine
(Figure 11).17

In addition to the muscles that are deep to the trapezius, the trapezius functions to stabilize and bend
the head and neck backward and laterally (Figure 12).17
IMPORTANT SAFETY INFORMATION (continued)
ADVERSE REACTIONS (continued) †
This is a hypothetical patient.
Chronic Migraine
The most frequently reported adverse reactions following injection of BOTOX® for chronic migraine vs
placebo include, respectively: neck pain (9% vs 3%), headache (5% vs 3%), eyelid ptosis (4% vs < 1%),
migraine (4% vs 3%), muscular weakness (4% vs < 1%), musculoskeletal stiffness (4% vs 1%), bronchitis
(3% vs 2%), injection-site pain (3% vs 2%), musculoskeletal pain (3% vs 1%), myalgia (3% vs 1%), facial
paresis (2% vs 0%), hypertension (2% vs 1%), and muscle spasms (2% vs 1%).
Severe worsening of migraine requiring hospitalization occurred in approximately 1% of BOTOX® treated
patients in study 1 and study 2, usually within the first week after treatment, compared with 0.3% of
placebo-treated patients.
22 Please see additional Important Safety Information about BOTOX® on following pages. 23
 Standard occipitalis PREEMPT protocol*
Dose1
• 5 Units (0.1 mL) in each site
• Total 30 Units divided into 6 sites
(3 on each side)

Injection site 1E1

• Palpate the occipital
protuberance and find the most
posterior point (inion) in the
midline (Figure 13)
• Locate the tip of the mastoid
process behind the ear (Figure 13)
• Place your thumb on the
midpoint of the occipital
protuberance (inion) and your
index finger on tip of the
mastoid process Occipital Nuchal ridge17,* Inion17,* Mastoid
protuberance17,* process17,*
• Divide the space between your
thumb and index finger in half
• Place the first injection just above
the nuchal ridge at this midpoint

Figure 13† Figure 14

Injection site 2E2
• Measure a diagonal fingerbreadth Additional factors to consider prior to injection
E2 E3 E3 E2
up and out toward the superior
helix of the ear (see diagram on • The occipitalis muscle is shallow
page 20) for the second muscle E1 E1 • Inject the most superficial aspect of the muscle, which will be just upon penetration of the dermis
area for injection (eg, at the (Figure 14)
10 o’clock position for the • Inject at 45º, angling the needle upward and away from the neck (Figure 14)
left injection)
• Injecting too low in the neck may result in neck pain and weakness; inject above the nuchal ridge
Note: The considerations above cannot eliminate the risk of adverse events following BOTOX® injections.
Injection site 3E3
†
This is a hypothetical patient.

• Measure a diagonal fingerbreadth IMPORTANT SAFETY INFORMATION (continued)

up and medial for the third ADVERSE REACTIONS (continued)
muscle area for injection (eg, at Post Marketing Experience
Occipitalis injection sites1
the 2 o’clock position for the There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia,
left injection) 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
*Muscles and anatomical structures shown for anatomical reference only. disease. The exact relationship of these events to the botulinum toxin injection has not been established.
24 Please see additional Important Safety Information about BOTOX® on following pages. 25
 Standard cervical paraspinal PREEMPT protocol*
Dose1
• 5 Units (0.1 mL) in each site
• Total 20 Units divided into 4 sites
(2 on each side)

Occipital protuberance
Injection site 1F1
• Measure about 1 cm left of the
midline of the cervical spine and
about 3 cm (≈ 2 fingerbreadths)
inferior to the lower border of the
occipital protuberance Do not inject below this line

Injection site 2F2

• Measure about 1.5 cm (≈ 1
fingerbreadth) diagonally up at a Cervical paraspinal muscle group17,* Occipital protuberance17,*
45º angle toward the helix of the
ear (see diagram on page 20) Figure 15
from the first injection site
Additional factors to consider prior to injection
• Assess patient for preexisting neck pain/weakness to help properly set expectations about this
muscle group
• Position the patient upright, with the head in a neutral position; flexing far forward may result in
injecting too deep
• Visualize a line across the neck, ≈ 2 fingerbreadths down from the occipital protuberance, and avoid
injecting below that line (Figure 15)
• Inject higher (in the hairline) to help minimize the potential for neck weakness—consider the area
F2 F2
the suboccipitalis region

F1 F1 • Inject in the most superficial aspect of the muscle, angling 45º and superiorly
• Penetrating the fascia should be sufficient to avoid injecting too deep
• Cervical paraspinal muscles are a group of muscles running deep to the cervical spine (see posterior
*Muscles and anatomical structures shown for anatomy on page 22 for details)
anatomical reference only.
Note: The considerations above cannot eliminate the risk of adverse events following BOTOX® injections.
Cervical paraspinal injection sites1
IMPORTANT SAFETY INFORMATION (continued)
DRUG INTERACTIONS
Co-administration of BOTOX® and aminoglycosides or other agents interfering with neuromuscular
transmission (eg, 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.
26 Please see additional Important Safety Information about BOTOX® on following pages. 27
 Standard trapezius PREEMPT protocol*
Dose1
• 5 Units (0.1 mL) in each site
• Total 30 Units divided into 6 sites
(3 on each side)

Injection site 1
G1

• Divide the upper portion of the

trapezius muscle in half, from
the inflection point of the neck
(necklace line) to the acromion
• The first injection is located at
this midpoint

Injection site 2
G2

• Split the difference between Acromion17,* Inflection point Trapezius muscle17,*

injection 1 and the acromion of neck
(necklace line)* Figure 16

Injection site 3
G3 Additional factors to consider prior to injection
• Split the difference between • Assess patient for possible preexisting neck/shoulder weakness to help properly set expectations
injection 1 and the necklace line about injecting this muscle
• Inject horizontal to the muscle to avoid injecting too deep (Figure 16)
• Inject the supraclavicular portion of the muscle, lateral to the neckline and medial to the deltoid/
acromion joint (Figure 16)
• Injecting too high into the cervical spine area or too deep may lead to neck weakness, pain, and
G3 G3
G1 compensatory muscle activity
G1
G2 G2 • Patients with small frames may be predisposed to weakness in this area
*Muscles and anatomical structures shown for
anatomical reference only.
Note: The considerations above cannot eliminate the risk of adverse events following BOTOX® injections.
Trapezius injection sites
1

IMPORTANT SAFETY INFORMATION (continued) Indication

DRUG INTERACTIONS (continued) Chronic Migraine
The effect of administering different botulinum neurotoxin products at the same time or within several BOTOX® for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine
(≥ 15 days per month with headache lasting 4 hours a day or longer).
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 Important Limitations
botulinum toxin. Excessive weakness may also be exaggerated by administration of a muscle relaxant Safety and effectiveness have not been established for the prophylaxis of episodic migraine
before or after administration of BOTOX®. (14 headache days or fewer per month) in 7 placebo-controlled studies.
Please see accompanying full Prescribing Information including Boxed Warning Please see Important Safety Information including Boxed Warning about BOTOX®
28 and Medication Guide. on following pages. 29
 Adverse events observed during PREEMPT pivotal trials1 Discontinuation rates due to adverse events1,20-22
Adverse reactions ≥ 5% in Chronic Migraine clinical trials were headache and neck pain (n = 687). Observed treatment-related adverse events were typically mild to moderate in severity.

BOTOX®
Placebo

4 1
Adverse Reactions by Body System 1

% %
155 Units to 195 Units
(n = 692)

VS
(n = 687)

Nervous system disorders Headache 32 (5%) 22 (3%) (26/687) (8/692)

Migraine 26 (4%) 18 (3%)
Facial paresis 15 (2%) 0 (0%)
BOTOX® Placebo
Eye disorders Eyelid ptosis 25 (4%) 2 (< 1%)

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

Musculoskeletal and Neck pain 60 (9%) 19 (3%)

connective-tissue Musculoskeletal stiffness 25 (4%) 6 (1%)
disorders Muscular weakness 24 (4%) 2 (< 1%)
Myalgia 21 (3%) 6 (1%)
Musculoskeletal pain 18 (3%) 10 (1%)
Muscle spasms 13 (2%) 6 (1%)

General disorders and

administration-site Injection-site pain 23 (3%) 14 (2%)
conditions

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

IMPORTANT SAFETY INFORMATION (continued)
CONTRAINDICATIONS
BOTOX® is contraindicated in the presence of infection at the proposed injection site(s) and in individuals
with known hypersensitivity to any botulinum toxin preparation or to any of the components in
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING the formulation.
WARNINGS AND PRECAUTIONS
WARNING: DISTANT SPREAD OF TOXIN EFFECT
Lack of Interchangeability Between Botulinum Toxin Products
Postmarketing reports indicate that the effects of BOTOX® and all botulinum toxin products The potency Units of BOTOX® are specific to the preparation and assay method utilized. They
may spread from the area of injection to produce symptoms consistent with botulinum toxin
are not interchangeable with other preparations of botulinum toxin products and, therefore,
effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia,
dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have Units of biological activity of BOTOX® cannot be compared to nor converted into Units of any
been reported hours to weeks after injection. Swallowing and breathing difficulties can be life other botulinum toxin products assessed with any other specific assay method.
threatening, and there have been reports of death. The risk of symptoms is probably greatest Spread of Toxin Effect
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 See Boxed Warning.
predispose them to these symptoms. In unapproved uses, including spasticity in children, and No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX® for
in approved indications, cases of spread of effect have been reported at doses comparable to chronic migraine at the labeled dose have been reported.
those used to treat cervical dystonia and upper limb spasticity and at lower doses.
30 Please see additional Important Safety Information about BOTOX® on following pages. 31
 Patient assessment before injection* Preexamination of the brow (continued)
Before any injections occur, patients should be evaluated for conditions that may be affected or Ptosis may be a preexisting condition or may occur after BOTOX® treatment. Patients should be
exacerbated by treatment. If any conditions are found to exist, the injector should inform and counsel evaluated for both eyelid and eyebrow ptosis.
the patient. Proper counseling will help set patient expectations. Patients with preexisting conditions
should be carefully assessed to determine if they’re appropriate for injection.
Unaffected Affected
PATIENT EXAMINATION:

✓ Visually inspect the muscle

✓ Ask the patient to activate the muscle

Figure 18† Figure 19 Figure 20†
✓ Palpate the muscle
Lid ptosis Medial brow ptosis Preexisting ptosis
Notice the asymmetry as a result Notice the medial brow Weakening of the levator muscle
Preexamination of the brow
of the drooping lid on the left.‡ depression and lateral brow is a common preexisting
What to look for: Inspect for excessive soft tissue resting near the upper lid of the eye and lid drooping elevation on the right.‡ condition leading to ptosis in
(Figure 17). older patients.23,‡

Preexamination of the forehead

What to look for: Brow ptosis, possibly
compensated by active frontalis muscles,
of which the patient may be unaware.

How to examine: Ask the patient to activate

the frontalis muscle by raising and lowering
her eyebrows (Figure 21). Observe the dynamic
muscle activity and whether there is any
compensatory mechanism keeping the eyelids Figure 21†
open in the presence of brow weakness.

Figure 17
†
This is a hypothetical patient.
‡ Muscles and anatomical structures shown for anatomical reference only.

*Muscles and anatomical structures shown for anatomical reference only.

IMPORTANT SAFETY INFORMATION (continued)

WARNINGS AND PRECAUTIONS (continued)
Serious Adverse Reactions With Unapproved Use IMPORTANT SAFETY INFORMATION (continued)
Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with WARNINGS AND PRECAUTIONS (continued)
some adverse reactions associated with fatal outcomes, have been reported in patients who received Hypersensitivity Reactions
BOTOX® injections for unapproved uses. In these cases, the adverse reactions were not necessarily related Serious and/or immediate hypersensitivity reactions have been reported. These reactions include
to distant spread of toxin, but may have resulted from the administration of BOTOX® to the site of injection anaphylaxis, serum sickness, urticaria, soft-tissue edema, and dyspnea. If such a reaction occurs, further
and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant injection of BOTOX® should be discontinued and appropriate medical therapy immediately instituted. One
disabilities. There is insufficient information to identify factors associated with an increased risk for adverse fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently
reactions associated with the unapproved uses of BOTOX®. The safety and effectiveness of BOTOX® for the causal agent cannot be reliably determined.
32 unapproved uses have not been established. Please see additional Important Safety Information about BOTOX® on following pages. 33
 Patient assessment before injection (continued)*
Preexamination of the neck How to examine: Observe the
patient, standing, in profile with
What to look for: Neck pain and
a neutral-spine position. Look for
neck weakness may be present
a plumb (vertical) line from the
among Chronic Migraine patients.24
tragus and anterior ridge of the
Inspect the patient for a
trapezius through the patient’s
head-forward position, which
center of gravity (Figure 23). If the
may indicate preexisting muscle
tragus is anterior to this line by 2
weakness (Figure 22).
to 3 fingerbreadths, this may be
abnormal (Figure 22).

Prior to BOTOX® injections, consider preexamining

patients for pain sensitivity in the neck.

Figure 22 †

Three-fingerbreadths’, head-forward position

*Muscles and anatomical structures shown for anatomical reference only.

†
This is a hypothetical patient.

‡ This is a hypothetical patient. Figure 23‡

IMPORTANT SAFETY INFORMATION (continued)

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued)
WARNINGS AND PRECAUTIONS (continued) Dysphagia and Breathing Difficulties
Pre-Existing Neuromuscular Disorders Treatment with BOTOX® and other botulinum toxin products can result in swallowing or breathing
Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to
junction disorders (eg, myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given these complications. In most cases, this is a consequence of weakening of muscles in the area of
botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing
effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia, (see Boxed Warning).
34 and respiratory compromise from therapeutic doses of BOTOX® (see Adverse Reactions). Please see additional Important Safety Information about BOTOX® on following pages. 35
 Managing patient expectations Tips to efficiently adopt BOTOX® in the office
BEFORE INJECTION Office staff and processes:
• Discuss goals of preventive vs acute therapy • Assign staff to specific roles
• Confirm a commitment to the entire treatment process ✓ Roles include ordering and submitting insurance verifications, prior authorizations, and claims
– Reinforce treatment as an ongoing plan, not a single procedure
– Communicate that treatment is every 12 weeks, with efficacy evaluated • Have a process to identify Chronic Migraine patients
at 24 weeks in clinical trials1 ✓ Use a screener and symptom assessment tool to document symptoms and medication history
• Assess the patient for preexisting conditions and counsel accordingly
• Talk about any concerns related to needles and discomfort • Use a system to track and schedule recurring treatment
– Providers may consider topical anesthetic on appropriate areas (eg, frontalis) ✓ Ensure patients receive treatment every 12 weeks
– Explain how the needle insertion may feel (eg, like a small pinprick sensation) ✓ Send reminders 1 to 2 weeks before the appointment

• Set up BOTOX® Clinic Days from the beginning

DURING INJECTION
✓ Improve patient flow and the efficiency of paperwork processing by having a dedicated time and
• Talk to patients as you perform injections place for procedures
• Ensure the patient is comfortable
– Switch needles frequently to avoid pain caused by dull needles • Consider involving additional office staff to help
✓ Include NPs/PAs for follow-ups, patient counseling, and injections
✓ Train nursing staff to reconstitute and prepare syringes of BOTOX®
AFTER INJECTION
• Reinforce the treatment schedule
– Preschedule patients to avoid missing treatments every 12 weeks
• Tell patients it may take time to notice a response
– Efficacy will be assessed at 24 weeks1 IMPORTANT SAFETY INFORMATION (continued)
• Plan for follow-up at 4 to 6 weeks to monitor progress and check for ADVERSE REACTIONS
adverse events The following adverse reactions to BOTOX® for injection are discussed in greater detail in the
following sections: Spread of Toxin Effect (see Boxed Warning); Hypersensitivity Reactions (see
Contraindications and Warnings and Precautions); Dysphagia and Breathing Difficulties (see Warnings
and Precautions).
Chronic Migraine
The most frequently reported adverse reactions following injection of BOTOX® for chronic migraine vs
placebo include, respectively: neck pain (9% vs 3%), headache (5% vs 3%), eyelid ptosis (4% vs < 1%),
migraine (4% vs 3%), muscular weakness (4% vs < 1%), musculoskeletal stiffness (4% vs 1%), bronchitis
IMPORTANT SAFETY INFORMATION (continued) (3% vs 2%), injection-site pain (3% vs 2%), musculoskeletal pain (3% vs 1%), myalgia (3% vs 1%), facial
WARNINGS AND PRECAUTIONS (continued) paresis (2% vs 0%), hypertension (2% vs 1%), and muscle spasms (2% vs 1%).
Human Albumin and Transmission of Viral Diseases
This product contains albumin, a derivative of human blood. Based on effective donor screening and Severe worsening of migraine requiring hospitalization occurred in approximately 1% of BOTOX® treated
product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. patients in study 1 and study 2, usually within the first week after treatment, compared with 0.3% of
A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely placebo-treated patients.
36 remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin. Please see additional Important Safety Information about BOTOX® on following pages. 37
 Tips to efficiently adopt BOTOX® in the office (continued) Your patients may already meet their insurance policy requirements for BOTOX®
Insurance documentation requirements:
Consult individual policies for specific requirements. Generally, you may need the following for Majority of lives require trial Chronic Migraine patients
insurance purposes: of 2 or fewer oral preventives25,* have tried

3.9
• Medication history

• Defined medical necessity

77.5%
• Services provided

• BOTOX® administration details (sites, Units, schedule) 9.7%

2 or fewer
3 or more
12.8%
• Clinical effectiveness and/or outcomes of BOTOX® therapy N/A preventive treatments
on average (n = 493)5
Based on data covering 244,831,608 medical lives.
Allergan is here to help
Ask about working with a Neuroscience Business Practice Specialist (NBPS)
for in-person advice on reimbursement. There should be no financial barriers to *As of Q2 2015.
patients accessing BOTOX® treatment.

Understanding oral preventive trial requirements

Some factors considered when determining adequate treatment trial include:
• Number of oral preventives needed
• Types of therapeutic classes
• Required duration of each treatment trial (if any)
• Whether medications with contraindications or intolerance concerns may count as a treatment trial
Check with individual payer policies for specific treatment trial requirements.

IMPORTANT SAFETY INFORMATION (continued)

DRUG INTERACTIONS
Co-administration of BOTOX® and aminoglycosides or other agents interfering with neuromuscular
transmission (eg, curare-like compounds) should only be performed with caution as the effect of the
IMPORTANT SAFETY INFORMATION (continued) toxin may be potentiated. Use of anticholinergic drugs after administration of BOTOX® may potentiate
ADVERSE REACTIONS (continued) systemic anticholinergic effects. The effect of administering different botulinum neurotoxin products at
Post Marketing Experience the same time or within several months of each other is unknown. Excessive neuromuscular weakness
There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a
and/or other significant debility or anaphylaxis, after treatment with botulinum toxin. There have also previously administered botulinum toxin. Excessive weakness may also be exaggerated by administration
been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial of a muscle relaxant before or after administration of BOTOX®.
infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular Please see accompanying full Prescribing Information including Boxed Warning
38 disease. The exact relationship of these events to the botulinum toxin injection has not been established. and Medication Guide. 39
 Resources available to your patients Resources available to injectors and the office
Ask your Allergan representative for more information about these resources or visit Office resources
BotoxAcademy.com to download or learn more. BOTOX® (onabotulinumtoxinA) treatment record
for Chronic Migraine patients Treatment record pad
BOTOX® for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥ 15 days per month with
headache lasting 4 hours a day or longer).
Important Limitations
Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month)

Helps record treatment information (sites, dose) for the injector and/or office staff.
in 7 placebo-controlled studies.

Patient education and financial assistance

Patient Name: _______________________________________________________________________ DOB: ____ / ____ / ____
Treatment Date: ____ / ____ / ____ Weeks since last treatment (if applicable): _______________________________________

Number of headache days/month—Current: _________________________________ Baseline (if applicable): _____________________

Number of headache hours/day—Current: __________________________________ Baseline (if applicable): _____________________
(When determining number of headache days, it may be beneficial to ask the patient how many headache-free days each month the patient is experiencing.)
Clinical rationale for BOTOX®:

Vial Size/NDC No. 200 Unit Vial/NDC No.: 00023-3921-02a 100 Unit Vial/NDC No.: 00023-1145-01a
Dilution (200 Units/4 mL or 100 Units/2 mL) Lot number(s) Vial expiration date(s)

■ Please check box if an SPP is used.

a
For electronic billing, payers require an 11-digit NDC number [5-4-2 configuration] to be reported on the claim form. Therefore, an additional zero should be added to the
beginning of the 10-digit NDC listed on the box [eg, 00023-3921-02].

BOTOX for Chronic Migraine patient brochure

BOTOX® Dosing by Muscle Areas for Chronic Migraine

® E. Occipitalis
BOTOX® dosage: 30 Units divided in
6 sites Right: ____ Left: ____

A. Corrugator C. Frontalis F. Cervical Paraspinal

BOTOX® dosage: 10 Units divided in BOTOX® dosage: 20 Units divided in BOTOX® dosage: 20 Units divided in
2 sites Right: ____ Left: ____ 4 sites Right: ____ Left: ____ 4 sites Right: ____ Left: ____

Introduction to treatment for patients considering BOTOX® as their next step.

B. Procerus D. Temporalis G. Trapezius
BOTOX® dosage: 5 Units in BOTOX® dosage: 40 Units divided in BOTOX® dosage: 30 Units divided in
1 site ___________________ 8 sites Right: ____ Left: ____ 6 sites Right: ____ Left: ____

Total Units injected: ____________________________________________________ Total Units discarded: ____________________

Physician signature: ____________________________________________________________________________________________

Please document patient response on reverse side

Also available in Spanish.

For adults with Chronic Migraine, 15 or more
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING
headache days a month, each lasting 4 hours or more,
WARNING: DISTANT SPREAD OF TOXIN EFFECT
BOTOX is the first and only
®
Postmarketing reports indicate that the effects of BOTOX® and all botulinum toxin products may spread from the area of
preventive treatment proven to 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
reduce headache days every month. 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
BOTOX® prevents up to 9 headache days a month, vs up to 7 days for placebo injection. would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications,
BOTOX® is a prescription medicine that is injected to prevent headaches in adults with Chronic Migraine who have 15 or more cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses.
days each month with headache lasting 4 or more hours each day in people 18 years or older. Please see additional Important Safety Information on reverse side.
It is not known whether BOTOX® is safe or effective to prevent headaches in patients with migraine who have 14 or fewer
headache days each month (episodic migraine).

IMPORTANT SAFETY INFORMATION

BOTOX® may cause serious side effects that can be life threatening. Call your doctor or get medical help right away if you have any
of these problems any time (hours to weeks) after injection of BOTOX®:
• Problems swallowing, speaking, or breathing, due to weakening of associated muscles, can be severe and result in loss of life. You
are at the highest risk if these problems are pre-existing before injection. Swallowing problems may last for several months
• Spread of toxin effects. The effect of botulinum toxin may affect areas away from the injection site and cause serious symptoms
including: loss of strength and all-over muscle weakness, double vision, blurred vision and drooping eyelids, hoarseness or change

Neuroscience Business Practice Specialists

or loss of voice (dysphonia), trouble saying words clearly (dysarthria), loss of bladder control, trouble breathing, trouble swallowing.
If this happens, do not drive a car, operate machinery, or do other dangerous activities
There has not been a confirmed serious case of spread of toxin effect away from the injection site when BOTOX® has been used at the
recommended dose to treat Chronic Migraine.
Please see additional Important Safety Information about BOTOX® inside.

!
C H R O N I C M I G R A I N E C H R O N I C M I G R A I N E

GETTING STARTED Getting Started With BOTOX® brochure These experts in BOTOX® reimbursement processes can walk you through
specific payer policies, as well as provide advice on operational efficiencies.
WITH BOTOX ®

TREATMENT

Information to help patients understand what to expect when starting treatment.

Hear from people living with BOTOX® is a prescription medicine that is injected to prevent
Chronic Migraine who have tried headaches in adults with chronic migraine who have 15 or
more days each month with headache lasting 4 or more
BOTOX® at BOTOXChronicMigraine.com hours each day in people 18 years or older.
It is not known whether BOTOX® is safe or effective to prevent
headaches in patients with migraine who have 14 or fewer
Indication headache days each month (episodic migraine).
BOTOX® (onabotulinumtoxinA) is a prescription medicine that is injected to prevent
headaches in adults with chronic migraine who have 15 or more days each month
with headache lasting 4 or more hours each day in people 18 years or older. You may be eligible for savings
It is not known whether BOTOX® is safe or effective to prevent headaches in patients on upcoming BOTOX® treatments.
with migraine who have 14 or fewer headache days each month (episodic migraine). Sign up at BOTOXSavingsCard.com
IMPORTANT SAFETY INFORMATION — Kelly
Real BOTOX® patient
Serious and/or immediate allergic reactions have been reported. These reactions 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 experience
any such symptoms; further injection of BOTOX® should be discontinued. IMPORTANT SAFETY INFORMATION
Please see additional Important Safety Information, including Boxed Warning, about BOTOX® inside and on front cover. BOTOX® may cause serious side effects that can be life threatening. Call your doctor or get medical help right away if you have any of these
problems any time (hours to weeks) after injection of BOTOX®:
References: 1. BOTOX® Prescribing Information, February 2014. 2. Lipton RB. Chronic migraine, classification, differential diagnosis, and epidemiology. Headache. 2011;51(suppl 2):77S-83S. 3. Hildreth CJ, Lynm • Problems swallowing, speaking, or breathing, due to weakening of associated muscles, can be severe and result in loss of life. You are at the
C, Glass RM. JAMA patient page. Migraine headache. JAMA. 2009;301(24):2608. 4. Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. 2nd ed. London, England: Martin Dunitz; 2002:69-111.
5. Aurora SK, Dodick DW, Turkel CC, et al; PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled highest risk if these problems are pre-existing before injection. Swallowing problems may last for several months
phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793-803. 6. Diener HC, Dodick DW, Aurora SK, et al; PREEMPT 2 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine:
results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804-814. 7. Data on file, Allergan, Inc., January 2013 to December 2013; BOTOX® Partnership
• Spread of toxin effects. The effect of botulinum toxin may affect areas away from the injection site and cause serious symptoms including: loss
for Access Program Activity. of strength and all-over muscle weakness, double vision, blurred vision and drooping eyelids, hoarseness or change or loss of voice (dysphonia),
All BOTOX® patients shown in this brochure were compensated for use of their image and their story.
trouble saying words clearly (dysarthria), loss of bladder control, trouble breathing, trouble swallowing. If this happens, do not drive a car,
operate machinery, or do other dangerous activities
There has not been a confirmed serious case of spread of toxin effect away from the injection site when BOTOX® has been used at the recommended
©2014 Allergan, Inc., Irvine, CA 92612 ® marks owned by Allergan, Inc. Dysport is a registered trademark of Ipsen Biopharm Limited. Myobloc is a registered trademark of Solstice Neurosciences, Inc. Prevention is a registered dose to treat chronic migraine.
trademark of Rodale Inc. Visa is a registered trademark of Visa International Service Association. Xeomin is a registered trademark of Merz Pharma GmbH & Co. KGaA. www.BOTOXChronicMigraine.com www.BOTOXSavingsCard.com
1-800-44-BOTOX Re-order: APC87MT14 141146 Please see additional Important Safety Information about BOTOX® inside.
September 18, 2014
Layout: sample BRM Env with IMB.lyt
Artwork for User Defined (5" x 7")

IMPORTANT: DO NOT ENLARGE, REDUCE OR MOVE the FIM and barcodes. They are only valid as printed!
to meet both USPS regulations and automation compatibility standards.
Special care must be taken to ensure FIM and barcode are actual size AND placed properly on the mail piece

YOUR ODDS
CHANGE

Peer-to-peer training
BOTOX HAS HELPED MANY PEOPLE.

Patient support program

®

SEE IF IT CAN HELP YOU TOO

FIRST-CLASS MAIL
BUSINESS REPLY MAIL

In clinical trials of people living with Chronic Migraine,

BOTOX® was proven to prevent up to 9 headache days
WEST CALDWELL NJ 07007-9706
PO BOX 6334
ALLERGAN CHRONIC MIGRAINE

a month (vs up to 7 with placebo injection) after

POSTAGE WILL BE PAID BY ADDRESSEE

2 treatments (at 24 weeks)1

‘‘
SIGN UP TO GET
PERMIT NO. 1543

Preceptorships, proctorships, and advanced group workshops are available to

‘‘
Patients receive treatment reminders and healthy-living tips from the editors of
SUPPORT FROM For many years, it seems I rarely had a day
PATHWAYS without a headache. Since my BO T OX®
TO PREVENTION treatments, I’ve noticed a definite difference.
Fill out and mail the
Authorized User, Serial #
(c) 1993-2012, DYMO Endicia, www.Endicia.com
Produced by DAZzle, Version 12.2.02

—April
W CALDWELL NJ

attached form to get Real BOTOX® patient

treatment reminders,
patient stories, and more!

Prevention ® magazine. Patients register at BOTOXChronicMigraine.com. help improve your technique.

Find out how BOTOX® may be able to
help you. Go to BOTOXChronicMigraine.com

IMPORTANT SAFETY INFORMATION (continued)

UNITED STATES

Serious and/or immediate allergic reactions have been reported. These reactions include
NO POSTAGE
NECESSARY
IF MAILED

itching, rash, red itchy welts, wheezing, asthma symptoms, or dizziness or feeling faint. Tell

155 12 31
IN THE

your doctor or get medical help right away if you experience any such symptoms; further
injection of BOTOX® should be discontinued.
Please see additional Important Safety Information on following pages. 3

TRACKING YOUR PROGRESS YOU’RE IN GOOD COMPANY

‘‘
Recording headache days can help you understand how
treatment is going
A headache day is any day you have headache symptoms for 4 hours or more.
Even if a headache isn’t severe, it can still count as a headache day.
‘‘
For me, one of the things I liked about BO T OX®
was the schedule — once every 12 weeks.
—April
STARTED
GETTING

Many people keep diaries or calendars to track the number and intensity of Real BOTOX® patient
headaches they experience. Your physician may have asked you to use one to help Be patient—it may take a few weeks to see results.
him or her find out if you have Chronic Migraine.
In clinical trials, BOTOX® treatment provided a significant reduction in headache days after
It can be helpful to keep a headache diary or calendar as you start treatment. the first treatment.5,6 After the second treatment (at 24 weeks), BOTOX® prevented up to
As you begin to have fewer headache days, you can keep track of your progress 9 headache days a month (vs up to 7 with placebo injection).1 This is why it is helpful to stay
and stay motivated. on a schedule when taking a preventive treatment like BOTOX®.

Committing to 2 treatment sessions is important.

Co-pay savings for commercially insured patients

You can find
a headache diary Your 1st 12 weeks*
Your 2nd 12
12 weeks
Seeing results

Online videos and education at BOTOXAcademy.com

treatment treatment weeks Based on your progress,
at
you and your doctor
BOTOXChronicMigraine.com will discuss re-treatment
You may begin to have fewer headache days every 12 weeks1

2 out of 3 new patients pay nothing out-of-pocket when they qualifyUNITS WEEKS SITES
When keeping a headache diary or The best way for you and your doctor to know if BOTOX® is meeting your treatment
calendar, it can be helpful to track goals is to give it time to work.
how many days per month you are *Your doctor may also ask you to make a follow-up appointment 4 weeks after your first treatment.
totally headache free.
IMPORTANT SAFETY INFORMATION (continued)

for the $250

Tell your doctor about all your medical conditions, including if you: have or have
had bleeding problems; have plans to have surgery; had surgery on your face;
—Elizabeth
weakness of forehead muscles, such as trouble raising your eyebrows; drooping

Register for ongoing education and to download tools for your office.
Real BOTOX®
IMPORTANT SAFETY INFORMATION (continued) eyelids; any other abnormal facial change; are pregnant or plan to become patient
Tell your doctor about all your muscle or nerve conditions such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), pregnant (it is not known if BOTOX® can harm your unborn baby); are breastfeeding
myasthenia gravis, or Lambert-Eaton syndrome, as you may be at increased risk of serious side effects including severe dysphagia or plan to breastfeed (it is not known if BOTOX® passes into breast milk).
12 (difficulty swallowing) and respiratory compromise (difficulty breathing) from typical doses of BOTOX®. Please see additional Important Safety Information on following pages. 5

MOST INSURANCE PLANS COVER

THE MAJORITY OF THE COST
OF BOTOX ®7,* ‘‘ We went over the risks and the benefits again and
we decided that it was the right option for me.
‘‘
—Kelly
Savings Program.26,*,†,‡ Visit AccessBSC.com for more information or to help
your patients enroll.
Real BOTOX® patient
You might even have the entire cost of your treatment
covered by insurance! You and your doctor will discuss the details
before your treatment, but here are a few things
to remember:
Insurance covers the whole cost
Visit • The injections take place in your doctor’s office
BOTOXSavingsCard.com That means you pay • The treatment session takes no longer than a regular doctor visit TM
to get started
Nothing Out of Pocket
THE DAY OF …

• There is no daily treatment

for BOTOX® treatment — Because BOTOX® is preventive, it is recommended that treatment be
given once every 12 weeks

OR
— Remember to schedule your next BOTOX® injection appointment with
your doctor in advance

Insurance covers some of the cost

You can use the

BOTOX® Savings Card IMPORTANT SAFETY INFORMATION (continued)

to help cover remaining out-of-pocket expenses Other side effects of BOTOX® (onabotulinumtoxinA) include: dry mouth, discomfort
or pain at the injection site, tiredness, headache, neck pain, and eye problems: double
*As of Q3 2013.
vision, blurred vision, decreased eyesight, drooping eyelids, swelling of your eyelids,
and dry eyes.

IMPORTANT SAFETY INFORMATION (continued) For more information refer to the Medication Guide or talk with your doctor.
Do not take BOTOX® if you: are allergic to any of the ingredients in BOTOX® (see Medication Guide for ingredients); had an allergic You are encouraged to report negative side effects of prescription drugs to the FDA.
reaction to any other botulinum toxin product such as Myobloc® (rimabotulinumtoxinB), Dysport® (abobotulinumtoxinA), or Xeomin® Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
(incobotulinumtoxinA); have a skin infection at the planned injection site. Full Product Information, including Boxed Warning and Medication Guide, has been
The dose of BOTOX® is not the same as, or comparable to, another botulinum toxin product. provided to your doctor. 7

Assistance for underinsured or uninsured patients

The BOTOX PATIENT ASSISTANCE® PROGRAM can help qualified patients with
the cost of BOTOX®.
Visit BOTOXReimbursementSolutions.com to download an application.

*Limitations apply. Please visit AccessBSC.com for full eligibility details.

†
66% of patients pay ≤ $250 out of pocket (OOP) before applying the Savings Program, meaning the $250 Savings Program covers the OOP costs.
The median OOP cost for all patients is $180 before applying the Savings Program.
‡
Current BOTOX® patients can receive up to $100 per treatment.

Indication IMPORTANT SAFETY INFORMATION (continued)

Chronic Migraine CONTRAINDICATIONS
BOTOX® for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine BOTOX® is contraindicated in the presence of infection at the proposed injection site(s) and in
(≥ 15 days per month with headache lasting 4 hours a day or longer). individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components
in the formulation.
Important Limitations
Safety and effectiveness have not been established for the prophylaxis of episodic migraine Please see Important Safety Information including Boxed Warning about BOTOX®
40 (14 headache days or fewer per month) in 7 placebo-controlled studies. throughout this brochure. 41
 Notes Notes page to come

Please see Important Safety Information including Boxed Warning about BOTOX®
42 throughout this brochure. 43
Helpful phone numbers and websites for you
ORDERING
AllerganDirect.com or call
1-800-44-BOTOX (1-800-442-6869), Option 1

CUSTOMER SERVICE
1-800-44-BOTOX (1-800-442-6869), Option 4

ALLERGAN MEDICAL INFORMATION LINE

1-800-433-8871

PATIENT FINANCIAL ASSISTANCE

For commercially insured patients:
AccessBSC.com
For uninsured or underinsured patients:
BOTOXReimbursementSolutions.com

PROFESSIONAL EDUCATION & RESOURCES

For injection training opportunities:
Contact your Allergan representative
For Neuroscience Business Practice Specialists:
Contact your Allergan representative
For injection and reconstitution videos, plus downloadable
patient education and more:
BOTOXAcademy.com

Please see Important Safety Information including Boxed Warning inside.

References:
1. BOTOX® Prescribing Information, August 2015. 2. Lipton RB. Chronic migraine, classification, differential diagnosis, and epidemiology. Headache. 2011;51
(suppl 2):77S-83S. 3. Dodick DW. Chronic daily headache. N Engl J Med. 2006;354(2):158-165. 4. Silberstein SD; US Headache Consortium. Practice
parameter: evidence-based guidelines for migraine headache (an evidence-based review). Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology. 2000;55(6):754-762. 5. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation
of prophylactic medications for episodic migraine and chronic migraine: results from the Second International Burden of Migraine Study (IBMS-II). Headache.
2013;53(4):644-655. 6. Holmes WF, MacGregor EA, Sawyer JPC, Lipton RB. Information about migraine disability influences physicians’ perceptions of illness
severity and treatment needs. Headache. 2001;41(4):343-350. 7. Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD. Assessment of migraine disability
using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache. 2003;43(4):336-342.
8. Dodick DW, Turkel CC, DeGryse RE, et al; PREEMPT Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results
from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921-936. 9. Blumenfeld A, Silberstein
SD, Dodick DW, Aurora SK, Turkel CC, Binder WJ. Method of injection of onabotulinumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment
paradigm based on the PREEMPT clinical program. Headache. 2010;50(9):1406-1418. 10. Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM.
Botulinum toxin type A (BOTOX®) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg. 2000;123(6):669-676. 11. Elkind
AH, O’Carroll P, Blumenfeld A, DeGryse R, Dimitrova R; for the BoNTA-024-026-036 Study Group. A series of three sequential, randomized, controlled studies
of repeated treatments with botulinum toxin type A for migraine prophylaxis. J Pain. 2006;7(10):688-696. 12. Saper JR, Mathew NT, Loder EW, DeGryse R,
VanDenburgh AM; for the BoNTA-009 Study Group. A double-blind, randomized, placebo-controlled comparison of botulinum toxin type A injection sites and
doses in the prevention of episodic migraine. Pain Med. 2007;8(6):478-485. 13. Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C; for the European
BoNTA Headache Study Group. A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type
A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia. 2007;27(6):492-503. 14. Aurora SK, Gawel M, Brandes JL, Pokta S, VanDenburgh
AM; BOTOX® North American Episodic Migraine Study Group. Botulinum toxin type A prophylactic treatment of episodic migraine: a randomized, double-blind,
placebo-controlled exploratory study. Headache. 2007;47(4):486-499. 15. Silberstein SD, Stark SR, Lucas SM, Christie SN, DeGryse RE, Turkel CC; BoNTA-039
Study Group. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin
Proc. 2005;80(9):1126-1137. 16. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C; BOTOX® CDH Study Group. Botulinum toxin type A
(BOTOX®) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(4):293-307.
17. Standring S, ed. Gray’s Anatomy: The Anatomical Basis of Clinical Practice. 40th ed. London, England: Churchill Livingstone; 2008. 18. Miloro M, Ghali GE,
Larsen P, Waite P. Peterson’s Principles of Oral and Maxillofacial Surgery. 3rd ed. Shelton, CT: People’s Medical Publishing-USA; 2011. 19. Stedman’s Medical
Dictionary. 28th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 20. Data on file, Allergan, Inc.; PREEMPT 1 Final Report. 21. Data on file, Allergan,
Inc.; PREEMPT 2 Final Report. 22. Data on file, Allergan, Inc.; Summary of Clinical Safety. 23. Baroody M, Holds JB, Vick VL. Advances in the diagnosis and
treatment of ptosis. Curr Opin Ophthalmol. 2005;16(6):351-355. 24. Calhoun AH, Ford S, Millen C, Finkel AG, Truong Y, Nie Y. The prevalence of neck pain in
migraine. Headache. 2010;50(8):1273-1277. 25. Data on file, Allergan, Inc.; Preventives Policy Analysis. 26. Data on file, Allergan, Inc., January to June 2014;
BOTOX ® Partnership for Access Program Activity.

© 2015 Allergan. All rights reserved. ® marks owned by Allergan, Inc. Prevention is a registered trademark of Rodale Inc.
BOTOXMedical.com/ChronicMigraine AccessBSC.com BOTOXReimbursementSolutions.com 1-800-44-BOTOX APC61DT15 152490
HIGHLIGHTS OF PRESCRIBING INFORMATION • A xillary Hyperhidrosis: 50 Units per axilla (2.7)
These highlights do not include all the information needed to use BOTOX® safely • Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected eye (2.8)
and effectively. See full prescribing information for BOTOX. • Strabismus: 1.25 Units-2.5 Units initially in any one muscle (2.9)
BOTOX (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor,
or intradermal use DOSAGE FORMS AND STRENGTHS
Initial U.S. Approval: 1989 Single-use, sterile 100 Units or 200 Units vacuum-dried powder for reconstitution only with
sterile, preservative-free 0.9% Sodium Chloride Injection USP prior to injection (3)
WARNING: DISTANT SPREAD OF TOXIN EFFECT
See full prescribing information for complete boxed warning. CONTRAINDICATIONS
The effects of BOTOX and all botulinum toxin products may spread from the area • H ypersensitivity to any botulinum toxin preparation or to any of the components in the
of injection to produce symptoms consistent with botulinum toxin effects. These formulation (4.1, 5.4, 6)
symptoms have been reported hours to weeks after injection. Swallowing and • Infection at the proposed injection site (4.2)
breathing difficulties can be life threatening and there have been reports of death. • Intradetrusor Injections: Urinary Tract Infection or Urinary Retention (4.3)
The risk of symptoms is probably greatest in children treated for spasticity but
symptoms can also occur in adults, particularly in those patients who have an WARNINGS AND PRECAUTIONS
underlying condition that would predispose them to these symptoms. (5.2) • P otency Units of BOTOX are not interchangeable with other preparations of botulinum
toxin products (5.1, 11)
RECENT MAJOR CHANGES • Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek
immediate medical attention if respiratory, speech or swallowing difficulties occur
• Indications and Usage, Upper Limb Spasticity (1.3) 04/2015
(5.2, 5.6)
• Dosage and Administration (2.1, 2.5) 04/2015
• Potential serious adverse reactions after BOTOX injections for unapproved uses (5.3)
• Warnings and Precautions, Serious Adverse Reactions with
• Concomitant neuromuscular disorder may exacerbate clinical effects of treatment (5.5)
Unapproved Use (5.3) 08/2015
• Use with caution in patients with compromised respiratory function (5.6, 5.7, 5.10)
INDICATIONS AND USAGE • Corneal exposure and ulceration due to reduced blinking may occur with BOTOX
BOTOX is an acetylcholine release inhibitor and a neuromuscular blocking agent treatment of blepharospasm (5.8)
indicated for: • Retrobulbar hemorrhages and compromised retinal circulation may occur with BOTOX
• Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, treatment of strabismus (5.9)
urgency, and frequency, in adults who have an inadequate response to or are intolerant • Bronchitis and upper respiratory tract infections in patients treated for upper limb
of an anticholinergic medication (1.1) spasticity (5.10)
• Treatment of urinary incontinence due to detrusor overactivity associated with a • Urinary tract infections in patients treated for OAB (5.12)
neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who • Urinary retention: Post-void residual urine volume should be monitored in patients
have an inadequate response to or are intolerant of an anticholinergic medication (1.1) treated for OAB or detrusor overactivity associated with a neurologic condition who
• Prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month do not catheterize routinely, particularly patients with multiple sclerosis or diabetes
with headache lasting 4 hours a day or longer) (1.2) mellitus. (5.13)
• Treatment of upper limb spasticity in adult patients (1.3)
ADVERSE REACTIONS
• Treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head
position and neck pain (1.4) The most common adverse reactions (≥5% and >placebo) are (6.1):
• Treatment of severe axillary hyperhidrosis that is inadequately managed by topical • OAB: urinary tract infection, dysuria, urinary retention
agents in adult patients (1.5) • Detrusor Overactivity associated with a neurologic condition: urinary tract infection,
• Treatment of blepharospasm associated with dystonia in patients ≥12 years of age (1.6) urinary retention
• Treatment of strabismus in patients ≥12 years of age (1.6) • Chronic Migraine: neck pain, headache
Important limitations: Safety and effectiveness of BOTOX have not been established for: • Spasticity: pain in extremity
• Prophylaxis of episodic migraine (14 headache days or fewer per month). (1.2) • Cervical Dystonia: dysphagia, upper respiratory infection, neck pain, headache, increased
• Treatment of upper limb spasticity in pediatric patients, and for the treatment of lower cough, flu syndrome, back pain, rhinitis
limb spasticity in adult and pediatric patients. (1.3) • Axillary Hyperhidrosis: injection site pain and hemorrhage, non-axillary sweating,
• Treatment of hyperhidrosis in body areas other than axillary. (1.5) pharyngitis, flu syndrome

DOSAGE AND ADMINISTRATION To report SUSPECTED ADVERSE REACTIONS, contact Allergan at

1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
• Follow indication-specific dosage and administration recommendations; Do not exceed a
total dose of 400 Units administered in a 3 month interval (2.1) DRUG INTERACTIONS
• See Preparation and Dilution Technique for instructions on BOTOX reconstitution, storage,
Patients receiving concomitant treatment of BOTOX and aminoglycosides or other agents
and preparation before injection (2.2)
interfering with neuromuscular transmission (e.g., curare-like agents), or muscle relaxants,
• Overactive Bladder: Recommended total dose 100 Units, as 0.5 mL (5 Units) injections should be observed closely because the effect of BOTOX may be potentiated (7)
across 20 sites into the detrusor (2.3)
• Detrusor Overactivity associated with a Neurologic Condition: Recommended total dose USE IN SPECIFIC POPULATIONS
200 Units, as 1 mL (~6.7 Units) injections across 30 sites into the detrusor (2.3) • P regnancy: Based on animal data, may cause fetal harm (8.1)
• Chronic Migraine: Recommended total dose 155 Units, as 0.1 mL (5 Units) injections per • Pediatric Use: Safety and efficacy are not established in patients under 18 years of
each site divided across 7 head/neck muscles (2.4) age for the prophylaxis of headaches in chronic migraine, treatment of OAB, detrusor
• Upper Limb Spasticity: Select dose based on muscles affected, severity of muscle overactivity associated with a neurologic condition, upper limb spasticity, and axillary
activity, prior response to treatment, and adverse event history; Electromyographic hyperhidrosis; in patients under 16 years of age for treatment of cervical dystonia; and in
guidance recommended (2.5) patients under 12 years of age for treatment of blepharospasm and strabismus (8.4)
• Cervical Dystonia: Base dosing on the patient’s head and neck position, localization of
pain, muscle hypertrophy, patient response, and adverse event history; use lower initial See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
dose in botulinum toxin naïve patients (2.6)
Revised: 08/2015

FULL PRESCRIBING INFORMATION: CONTENTS* 2 DOSAGE AND ADMINISTRATION

WARNING: DISTANT SPREAD OF TOXIN EFFECT 2.1 Instructions for Safe Use
1 INDICATIONS AND USAGE 2.2 Preparation and Dilution Technique
1.1 Bladder Dysfunction 2.3 Bladder Dysfunction
1.2 Chronic Migraine 2.4 Chronic Migraine
1.3 Upper Limb Spasticity 2.5 Upper Limb Spasticity
1.4 Cervical Dystonia 2.6 Cervical Dystonia
1.5 Primary Axillary Hyperhidrosis 2.7 Primary Axillary Hyperhidrosis
1.6 Blepharospasm and Strabismus 2.8 Blepharospasm
2.9 Strabismus
 3 DOSAGE FORMS AND STRENGTHS 7 DRUG INTERACTIONS
4 CONTRAINDICATIONS 7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission
4.1 Known Hypersensitivity to Botulinum Toxin 7.2 Anticholinergic Drugs
4.2 Infection at the Injection Site(s) 7.3 Other Botulinum Neurotoxin Products
4.3 Urinary Tract Infection or Urinary Retention 7.4 Muscle Relaxants
5 WARNINGS AND PRECAUTIONS 8 USE IN SPECIFIC POPULATIONS
5.1 Lack of Interchangeability between Botulinum Toxin Products 8.1 Pregnancy
5.2 Spread of Toxin Effect 8.3 Nursing Mothers
5.3 Serious Adverse Reactions with Unapproved Use 8.4 Pediatric Use
5.4 Hypersensitivity Reactions 8.5 Geriatric Use
5.5 Pre-Existing Neuromuscular Disorders 10 OVERDOSAGE
5.6 Dysphagia and Breathing Difficulties 11 DESCRIPTION
5.7 Pulmonary Effects of BOTOX in Patients with Compromised Respiratory 12 CLINICAL PHARMACOLOGY
Status Treated for Spasticity or for Detrusor Overactivity associated with 12.1 Mechanism of Action
a Neurologic Condition 12.3 Pharmacokinetics
5.8 Corneal Exposure and Ulceration in Patients Treated with BOTOX for 13 NONCLINICAL TOXICOLOGY
Blepharospasm 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.9 Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus 13.2 Animal Toxicology
5.10 Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity 14 CLINICAL STUDIES
5.11 Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity associated with 14.1 Overactive Bladder (OAB)
a Neurologic Condition 14.2 Detrusor Overactivity associated with a Neurologic Condition
5.12 Urinary Tract Infections in Patients with Overactive Bladder 14.3 Chronic Migraine
5.13 Urinary Retention in Patients Treated for Bladder Dysfunction 14.4 Upper Limb Spasticity
5.14 Human Albumin and Transmission of Viral Diseases 14.5 Cervical Dystonia
6 ADVERSE REACTIONS 14.6 Primary Axillary Hyperhidrosis
6.1 Clinical Trials Experience 14.7 Blepharospasm
6.2 Immunogenicity 14.8 Strabismus
6.3 Post-Marketing Experience 16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION 1.5 Primary Axillary Hyperhidrosis

BOTOX is indicated for the treatment of severe primary axillary hyperhidrosis that is
WARNING: DISTANT SPREAD OF TOXIN EFFECT inadequately managed with topical agents.
Postmarketing reports indicate that the effects of BOTOX and all botulinum toxin Important limitations
products may spread from the area of injection to produce symptoms consistent The safety and effectiveness of BOTOX for hyperhidrosis in other body areas have not been
with botulinum toxin effects. These may include asthenia, generalized muscle established. Weakness of hand muscles and blepharoptosis may occur in patients who
weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence receive BOTOX for palmar hyperhidrosis and facial hyperhidrosis, respectively. Patients
and breathing difficulties. These symptoms have been reported hours to weeks should be evaluated for potential causes of secondary hyperhidrosis (e.g., hyperthyroidism)
after injection. Swallowing and breathing difficulties can be life threatening and to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of
there have been reports of death. The risk of symptoms is probably greatest in the underlying disease.
children treated for spasticity but symptoms can also occur in adults treated Safety and effectiveness of BOTOX have not been established for the treatment of axillary
for spasticity and other conditions, particularly in those patients who have hyperhidrosis in pediatric patients under age 18.
an underlying condition that would predispose them to these symptoms. In
unapproved uses, including spasticity in children, and in approved indications, 1.6 Blepharospasm and Strabismus
cases of spread of effect have been reported at doses comparable to those used BOTOX is indicated for the treatment of strabismus and blepharospasm associated with
to treat cervical dystonia and upper limb spasticity and at lower doses. [See dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12
Warnings and Precautions (5.2)] years of age and above.
2 DOSAGE AND ADMINISTRATION
1 INDICATIONS AND USAGE 2.1 Instructions for Safe Use
1.1 Bladder Dysfunction The potency Units of BOTOX (onabotulinumtoxinA) for injection are specific to the
Overactive Bladder preparation and assay method utilized. They are not interchangeable with other
BOTOX (onabotulinumtoxinA) for injection is indicated for the treatment of overactive preparations of botulinum toxin products and, therefore, units of biological activity of
bladder with symptoms of urge urinary incontinence, urgency, and frequency, in adults who BOTOX cannot be compared to nor converted into units of any other botulinum toxin
have an inadequate response to or are intolerant of an anticholinergic medication. products assessed with any other specific assay method [see Warnings and Precautions
Detrusor Overactivity associated with a Neurologic Condition (5.1) and Description (11)].
BOTOX is indicated for the treatment of urinary incontinence due to detrusor overactivity Indication specific dosage and administration recommendations should be followed.
associated with a neurologic condition (e.g., SCI, MS) in adults who have an inadequate When initiating treatment, the lowest recommended dose should be used. In treating adult
response to or are intolerant of an anticholinergic medication. patients for one or more indications, the maximum cumulative dose should not exceed
1.2 Chronic Migraine 400 Units, in a 3 month interval.
BOTOX is indicated for the prophylaxis of headaches in adult patients with chronic migraine The safe and effective use of BOTOX depends upon proper storage of the product,
(≥15 days per month with headache lasting 4 hours a day or longer). selection of the correct dose, and proper reconstitution and administration techniques. An
Important limitations understanding of standard electromyographic techniques is also required for treatment of
Safety and effectiveness have not been established for the prophylaxis of episodic migraine strabismus and of upper limb spasticity, and may be useful for the treatment of cervical
(14 headache days or fewer per month) in seven placebo-controlled studies. dystonia. Physicians administering BOTOX must understand the relevant neuromuscular
1.3 Upper Limb Spasticity and structural anatomy of the area involved and any alterations to the anatomy due to prior
surgical procedures and disease, especially when injecting near the lungs.
BOTOX is indicated for the treatment of upper limb spasticity in adult patients, to decrease
the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi 2.2 Preparation and Dilution Technique
radialis and flexor carpi ulnaris), finger flexors (flexor digitorum profundus and flexor Prior to injection, reconstitute each vacuum-dried vial of BOTOX with only sterile,
digitorum sublimis), and thumb flexors (adductor pollicis and flexor pollicis longus). preservative-free 0.9% Sodium Chloride Injection USP. Draw up the proper amount of
diluent in the appropriate size syringe (see Table 1, or for specific instructions for detrusor
Important limitations
overactivity associated with a neurologic condition see Section 2.3), and slowly inject
Safety and effectiveness of BOTOX have not been established for the treatment of other
the diluent into the vial. Discard the vial if a vacuum does not pull the diluent into the
upper limb muscle groups, or for the treatment of lower limb spasticity. Safety and
vial. Gently mix BOTOX with the saline by rotating the vial. Record the date and time of
effectiveness of BOTOX have not been established for the treatment of spasticity in pediatric
reconstitution on the space on the label. BOTOX should be administered within 24 hours
patients under age 18 years. BOTOX has not been shown to improve upper extremity
after reconstitution. During this time period, reconstituted BOTOX should be stored in a
functional abilities, or range of motion at a joint affected by a fixed contracture. Treatment
refrigerator (2° to 8°C).
with BOTOX is not intended to substitute for usual standard of care rehabilitation regimens.
1.4 Cervical Dystonia
BOTOX is indicated for the treatment of adults with cervical dystonia, to reduce the severity
of abnormal head position and neck pain associated with cervical dystonia.
Table 1: Dilution Instructions for BOTOX Vials (100 Units and 200 Units)** Detrusor Overactivity associated with a Neurologic Condition
An intravesical instillation of diluted local anesthetic with or without sedation, or general
Diluent* Added to Resulting Dose Diluent* Added to Resulting Dose anesthesia may be used prior to injection, per local site practice. If a local anesthetic
100 Unit Vial Units per 0.1 mL 200 Unit Vial Units per 0.1 mL instillation is performed, the bladder should be drained and irrigated with sterile saline
1 mL 10 Units 1 mL 20 Units before injection.
2 mL 5 Units 2 mL 10 Units The recommended dose is 200 Units of BOTOX per treatment, and should not be exceeded.
4 mL 2.5 Units 4 mL 5 Units 200 Unit Vial of BOTOX
8 mL 1.25 Units 8 mL 2.5 Units • Reconstitute a 200 Unit vial of BOTOX with 6 mL of preservative-free 0.9% Sodium
10 mL 1 Unit 10 mL 2 Units Chloride Injection, USP and mix the vial gently.
• Draw 2 mL from the vial into each of three 10 mL syringes.
* Preservative-free 0.9% Sodium Chloride Injection, USP Only • Complete the reconstitution by adding 8 mL of preservative-free 0.9% Sodium Chloride
** For Detrusor Overactivity associated with a Neurologic Condition Dilution see Section 2.3 Injection, USP into each of the 10 mL syringes, and mix gently. This will result in three
Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of
increase in the BOTOX dose is also possible by administering a smaller or larger injection reconstituted BOTOX.
volume - from 0.05 mL (50% decrease in dose) to 0.15 mL (50% increase in dose). • Use immediately after reconstitution in the syringe. Dispose of any unused saline.
An injection of BOTOX is prepared by drawing into an appropriately sized sterile syringe 100 Unit Vial of BOTOX
an amount of the properly reconstituted toxin slightly greater than the intended dose. Air • Reconstitute two 100 Unit vials of BOTOX, each with 6 mL of preservative-free 0.9%
bubbles in the syringe barrel are expelled and the syringe is attached to an appropriate Sodium Chloride Injection, USP and mix the vials gently.
injection needle. Patency of the needle should be confirmed. A new, sterile needle and • Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL
syringe should be used to enter the vial on each occasion for removal of BOTOX. from each vial into a third 10 mL syringe for a total of 4 mL in each syringe.
Reconstituted BOTOX should be clear, colorless, and free of particulate matter. Parenteral • Complete the reconstitution by adding 6 mL of preservative-free 0.9% Sodium Chloride
drug products should be inspected visually for particulate matter and discoloration prior to Injection, USP into each of the 10 mL syringes, and mix gently. This will result in three
administration and whenever the solution and the container permit. 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of
2.3 Bladder Dysfunction reconstituted BOTOX.
General • Use immediately after reconstitution in the syringe. Dispose of any unused saline.
Patients must not have a urinary tract infection (UTI) at the time of treatment. Prophylactic Reconstituted BOTOX (200 Units/30 mL) is injected into the detrusor muscle via a flexible or
antibiotics, except aminoglycosides, [see Drug Interactions (7.1)] should be administered rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to
1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment to reduce the achieve adequate visualization for the injections, but over-distension should be avoided.
likelihood of procedure-related UTI. The injection needle should be filled (primed) with approximately 1 mL of reconstituted
Patients should discontinue anti-platelet therapy at least 3 days before the injection BOTOX prior to the start of injections (depending on the needle length) to remove any air.
procedure. Patients on anti-coagulant therapy need to be managed appropriately to The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of
decrease the risk of bleeding. 1 mL (~6.7 Units) each (total volume of 30 mL) should be spaced approximately 1 cm apart
Appropriate caution should be exercised when performing a cystoscopy. (see Figure 1). For the final injection, approximately 1 mL of sterile normal saline should
Overactive Bladder be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the
An intravesical instillation of diluted local anesthetic with or without sedation may be used injections are given, the saline used for bladder wall visualization should be drained. The
prior to injection, per local site practice. If a local anesthetic instillation is performed, the patient should be observed for at least 30 minutes post-injection.
bladder should be drained and irrigated with sterile saline before injection. Patients should be considered for re-injection when the clinical effect of the previous
The recommended dose is 100 Units of BOTOX, and is the maximum recommended dose. injection diminishes (median time to qualification for re-treatment in the double-blind,
The recommended dilution is 100 Units/10 mL with preservative-free 0.9% Sodium Chloride placebo-controlled clinical studies was 295-337 days [42-48 weeks] for BOTOX 200 Units),
Injection, USP (see Table 1). Dispose of any unused saline. but no sooner than 12 weeks from the prior bladder injection.
Reconstituted BOTOX (100 Units/10 mL) is injected into the detrusor muscle via a flexible or 2.4 Chronic Migraine
rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to The recommended dilution is 200 Units/4 mL or 100 Units/2 mL, with a final concentration
achieve adequate visualization for the injections, but over-distension should be avoided. of 5 Units per 0.1 mL (see Table 1). The recommended dose for treating chronic migraine
is 155 Units administered intramuscularly using a sterile 30-gauge, 0.5 inch needle as
The injection needle should be filled (primed) with approximately 1 mL of reconstituted 0.1 mL (5 Units) injections per each site. Injections should be divided across 7 specific
BOTOX prior to the start of injections (depending on the needle length) to remove any air. head/neck muscle areas as specified in the diagrams and Table 2 below. A one inch needle
The needle should be inserted approximately 2 mm into the detrusor, and 20 injections may be needed in the neck region for patients with thick neck muscles. With the exception
of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart (see of the procerus muscle, which should be injected at one site (midline), all muscles should be
Figure 1). For the final injection, approximately 1 mL of sterile normal saline should be injected bilaterally with half the number of injection sites administered to the left, and half
injected so that the remaining BOTOX in the needle is delivered to the bladder. After the to the right side of the head and neck. The recommended re-treatment schedule is every
injections are given, patients should demonstrate their ability to void prior to leaving the 12 weeks.
clinic. The patient should be observed for at least 30 minutes post-injection and until a Diagrams 1-4: Recommended Injection Sites (A through G) for Chronic Migraine
spontaneous void has occurred.
Patients should be considered for reinjection when the clinical effect of the previous 1 2 3 4
injection has diminished (median time until patients qualified for the second treatment of
BOTOX in double-blind, placebo-controlled clinical studies was 169 days [~24 weeks]), but
no sooner than 12 weeks from the prior bladder injection.
Figure 1: Injection Pattern for Intradetrusor Injections for Treatment of Overactive
Bladder and Detrusor Overactivity associated with a Neurologic Condition

A. Corrugator: D. Temporalis: E. Occipitalis: F. Cervical

5 U each side 20 U each side 15 U each side paraspinal:
10 U each side
B. Procerus: G. Trapezius:
5 U (one site) 15 U each side
C. Frontalis:
10 U each side
Table 2: BOTOX Dosing by Muscle for Chronic Migraine Dosing in initial and sequential treatment sessions should be tailored to the individual
patient based on the patient’s head and neck position, localization of pain, muscle
Head/Neck Area Recommended Dose (Number of Sites ) a
hypertrophy, patient response, and adverse event history. The initial dose for a patient
Frontalisb 20 Units divided in 4 sites without prior use of BOTOX should be at a lower dose, with subsequent dosing adjusted
based on individual response. Limiting the total dose injected into the sternocleidomastoid
Corrugator b
10 Units divided in 2 sites muscle to 100 Units or less may decrease the occurrence of dysphagia [see Warnings and
Procerus 5 Units in 1 site Precautions (5.2, 5.5, 5.6)].
Occipitalis b
30 Units divided in 6 sites The recommended dilution is 200 Units/2 mL, 200 Units/4 mL, 100 Units/1 mL, or 100
Units/2 mL with preservative-free 0.9% Sodium Chloride Injection, USP, depending on
Temporalisb 40 Units divided in 8 sites volume and number of injection sites desired to achieve treatment objectives (see Table 1).
Trapezius b
30 Units divided in 6 sites In general, no more than 50 Units per site should be administered. An appropriately sized
needle (e.g., 25-30 gauge) may be used for superficial muscles, and a longer 22 gauge
Cervical Paraspinal Muscle Groupb 20 Units divided in 4 sites needle may be used for deeper musculature. Localization of the involved muscles with
electromyographic guidance may be useful.
Total Dose: 155 Units divided in 31 sites
Clinical improvement generally begins within the first two weeks after injection with
Each IM injection site = 0.1 mL = 5 Units BOTOX
a
maximum clinical benefit at approximately six weeks post-injection. In the double-blind,
b
Dose distributed bilaterally placebo-controlled study most subjects were observed to have returned to pre-treatment
2.5 Upper Limb Spasticity status by 3 months post-treatment.
Dosing in initial and sequential treatment sessions should be tailored to the individual based 2.7 Primary Axillary Hyperhidrosis
on the size, number and location of muscles involved, severity of spasticity, the presence The recommended dose is 50 Units per axilla. The hyperhidrotic area to be injected should
of local muscle weakness, the patient’s response to previous treatment, or adverse event be defined using standard staining techniques, e.g., Minor’s Iodine-Starch Test. The
history with BOTOX. In clinical trials, doses ranging from 75 Units to 400 Units were divided recommended dilution is 100 Units/4 mL with 0.9% preservative-free sterile saline
among selected muscles (see Table 3 and Figure 2) at a given treatment session. (see Table 1). Using a 30 gauge needle, 50 Units of BOTOX (2 mL) is injected intradermally
in 0.1 to 0.2 mL aliquots to each axilla evenly distributed in multiple sites (10-15)
Table 3: BOTOX Dosing by Muscle for Upper Limb Spasticity approximately 1-2 cm apart.
Recommended Dose Repeat injections for hyperhidrosis should be administered when the clinical effect of a
Muscle previous injection diminishes.
Total Dosage (Number of Sites)
Biceps Brachii 100 Units-200 Units divided in 4 sites Instructions for the Minor’s Iodine-Starch Test Procedure:
Patients should shave underarms and abstain from use of over-the-counter deodorants or
Flexor Carpi Radialis 12.5 Units-50 Units in 1 site antiperspirants for 24 hours prior to the test. Patient should be resting comfortably without
Flexor Carpi Ulnaris 12.5 Units-50 Units in 1 site exercise, hot drinks for approximately 30 minutes prior to the test. Dry the underarm area
and then immediately paint it with iodine solution. Allow the area to dry, then lightly sprinkle
Flexor Digitorum Profundus 30 Units-50 Units in 1 site the area with starch powder. Gently blow off any excess starch powder. The hyperhidrotic
Flexor Digitorum Sublimis 30 Units-50 Units in 1 site area will develop a deep blue-black color over approximately 10 minutes.
Each injection site has a ring of effect of up to approximately 2 cm in diameter. To minimize
Adductor Pollicis 20 Units in 1 site the area of no effect, the injection sites should be evenly spaced as shown in Figure 3.
Flexor Pollicis Longus 20 Units in 1 site Figure 3: Injection Pattern for Primary Axillary Hyperhidrosis

Figure 2: Injection Sites for Upper Limb Spasticity

Biceps brachii
Each dose is injected to a depth of approximately 2 mm and at a 45° angle to the skin
surface, with the bevel side up to minimize leakage and to ensure the injections remain
Flexor carpi ulnaris intradermal. If injection sites are marked in ink, do not inject BOTOX directly through the ink
mark to avoid a permanent tattoo effect.
Flexor carpi radialis
2.8 Blepharospasm
Flexor digitorum sublimis For blepharospasm, reconstituted BOTOX is injected using a sterile, 27-30 gauge needle
(flexor digitorum superficialis) without electromyographic guidance. The initial recommended dose is 1.25 Units-2.5 Units
Flexor digitorum (0.05 mL to 0.1 mL volume at each site) injected into the medial and lateral pre-tarsal
profundus orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower
lid. Avoiding injection near the levator palpebrae superioris may reduce the complication of
Flexor pollicis ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior
longus oblique, may reduce the complication of diplopia. Ecchymosis occurs easily in the soft
Adductor eyelid tissues. This can be prevented by applying pressure at the injection site immediately
pollicis after the injection.
The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5 Units it is
100 Units/4 mL (see Table 1).
The recommended dilution is 200 Units/4 mL or 100 Units/2 mL with preservative-free In general, the initial effect of the injections is seen within three days and reaches a peak
0.9% Sodium Chloride Injection, USP (see Table 1). The lowest recommended starting dose at one to two weeks post-treatment. Each treatment lasts approximately three months,
should be used, and no more than 50 Units per site should generally be administered. An following which the procedure can be repeated. At repeat treatment sessions, the dose
appropriately sized needle (e.g., 25-30 gauge) may be used for superficial muscles, and a may be increased up to two-fold if the response from the initial treatment is considered
longer 22 gauge needle may be used for deeper musculature. Localization of the involved insufficient, usually defined as an effect that does not last longer than two months.
muscles with techniques such as needle electromyographic guidance or nerve stimulation However, there appears to be little benefit obtainable from injecting more than 5 Units
is recommended. per site. Some tolerance may be found when BOTOX is used in treating blepharospasm if
Repeat BOTOX treatment may be administered when the effect of a previous injection has treatments are given any more frequently than every three months, and is rare to have the
diminished, but generally no sooner than 12 weeks after the previous injection. The degree effect be permanent.
and pattern of muscle spasticity at the time of re-injection may necessitate alterations in The cumulative dose of BOTOX treatment for blepharospasm in a 30-day period should not
the dose of BOTOX and muscles to be injected. exceed 200 Units.
2.6 Cervical Dystonia 2.9 Strabismus
A double-blind, placebo-controlled study enrolled patients who had extended histories of BOTOX is intended for injection into extraocular muscles utilizing the electrical activity
receiving and tolerating BOTOX injections, with prior individualized adjustment of dose. recorded from the tip of the injection needle as a guide to placement within the target
The mean BOTOX dose administered to patients in this study was 236 Units (25th to 75th muscle. Injection without surgical exposure or electromyographic guidance should not be
percentile range of 198 Units to 300 Units). The BOTOX dose was divided among the attempted. Physicians should be familiar with electromyographic technique.
affected muscles [see Clinical Studies (14.5)].
To prepare the eye for BOTOX injection, it is recommended that several drops of a local
anesthetic and an ocular decongestant be given several minutes prior to injection.
The volume of BOTOX injected for treatment of strabismus should be between
0.05-0.15 mL per muscle.
The initial listed doses of the reconstituted BOTOX [see Dosage and Administration (2.2)] 5.3 Serious Adverse Reactions with Unapproved Use
typically create paralysis of the injected muscles beginning one to two days after injection Serious adverse reactions, including excessive weakness, dysphagia, and aspiration
and increasing in intensity during the first week. The paralysis lasts for 2-6 weeks and pneumonia, with some adverse reactions associated with fatal outcomes, have been
gradually resolves over a similar time period. Overcorrections lasting over six months have reported in patients who received BOTOX injections for unapproved uses. In these cases,
been rare. About one half of patients will require subsequent doses because of inadequate the adverse reactions were not necessarily related to distant spread of toxin, but may
paralytic response of the muscle to the initial dose, or because of mechanical factors such have resulted from the administration of BOTOX to the site of injection and/or adjacent
as large deviations or restrictions, or because of the lack of binocular motor fusion to structures. In several of the cases, patients had pre-existing dysphagia or other significant
stabilize the alignment. disabilities. There is insufficient information to identify factors associated with an increased
Initial doses in Units risk for adverse reactions associated with the unapproved uses of BOTOX. The safety and
Use the lower listed doses for treatment of small deviations. Use the larger doses only for effectiveness of BOTOX for unapproved uses have not been established.
large deviations. 5.4 Hypersensitivity Reactions
• For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1.25 Serious and/or immediate hypersensitivity reactions have been reported. These reactions
Units-2.5 Units in any one muscle. include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such
• For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2.5 Units-5 Units in a reaction occurs, further injection of BOTOX should be discontinued and appropriate
any one muscle. medical therapy immediately instituted. One fatal case of anaphylaxis has been reported
• For persistent VI nerve palsy of one month or longer duration: 1.25 Units-2.5 Units in in which lidocaine was used as the diluent, and consequently the causal agent cannot be
the medial rectus muscle. reliably determined.
Subsequent doses for residual or recurrent strabismus 5.5 Pre-Existing Neuromuscular Disorders
• It is recommended that patients be re-examined 7-14 days after each injection to Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or
assess the effect of that dose. neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome)
• Patients experiencing adequate paralysis of the target muscle that require subsequent should be monitored when given botulinum toxin. Patients with neuromuscular disorders
injections should receive a dose comparable to the initial dose. may be at increased risk of clinically significant effects including generalized muscle
• Subsequent doses for patients experiencing incomplete paralysis of the target muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory
may be increased up to two-fold compared to the previously administered dose. compromise from therapeutic doses of BOTOX [see Adverse Reactions (6.1)].
• Subsequent injections should not be administered until the effects of the previous 5.6 Dysphagia and Breathing Difficulties
dose have dissipated as evidenced by substantial function in the injected and Treatment with BOTOX and other botulinum toxin products can result in swallowing or
adjacent muscles. breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be
• The maximum recommended dose as a single injection for any one muscle is more susceptible to these complications. In most cases, this is a consequence of weakening
25 Units. of muscles in the area of injection that are involved in breathing or oropharyngeal muscles
that control swallowing or breathing [see Warnings and Precautions (5.2)].
The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5 Units it is
100 Units/4 mL (see Table 1). Deaths as a complication of severe dysphagia have been reported after treatment with
botulinum toxin. Dysphagia may persist for several months, and require use of a feeding
3 DOSAGE FORMS AND STRENGTHS tube to maintain adequate nutrition and hydration. Aspiration may result from severe
Single-use, sterile 100 Units or 200 Units vacuum-dried powder for reconstitution only with dysphagia and is a particular risk when treating patients in whom swallowing or respiratory
sterile, preservative-free 0.9% Sodium Chloride Injection USP prior to injection. function is already compromised.
4 CONTRAINDICATIONS Treatment with botulinum toxins may weaken neck muscles that serve as accessory
4.1 Known Hypersensitivity to Botulinum Toxin muscles of ventilation. This may result in a critical loss of breathing capacity in patients
BOTOX is contraindicated in patients who are hypersensitive to any botulinum toxin with respiratory disorders who may have become dependent upon these accessory
preparation or to any of the components in the formulation [see Warnings and muscles. There have been postmarketing reports of serious breathing difficulties, including
Precautions (5.4)]. respiratory failure.
4.2 Infection at the Injection Site(s) Patients with smaller neck muscle mass and patients who require bilateral injections into
BOTOX is contraindicated in the presence of infection at the proposed injection site(s). the sternocleidomastoid muscle for the treatment of cervical dystonia have been reported
4.3 Urinary Tract Infection or Urinary Retention to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid
Intradetrusor injection of BOTOX is contraindicated in patients with overactive bladder muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may
or detrusor overactivity associated with a neurologic condition who have a urinary tract be associated with an increased risk of upper respiratory infection and dysphagia.
infection. Intradetrusor injection of BOTOX is also contraindicated in patients with urinary Patients treated with botulinum toxin may require immediate medical attention should
retention and in patients with post-void residual (PVR) urine volume >200 mL, who are not they develop problems with swallowing, speech or respiratory disorders. These reactions
routinely performing clean intermittent self-catheterization (CIC). can occur within hours to weeks after injection with botulinum toxin [see Warnings and
5 WARNINGS AND PRECAUTIONS Precautions (5.2) and Adverse Reactions (6.1)].
5.1 Lack of Interchangeability between Botulinum Toxin Products 5.7 Pulmonary Effects of BOTOX in Patients with Compromised Respiratory
The potency Units of BOTOX are specific to the preparation and assay method utilized. They Status Treated for Spasticity or for Detrusor Overactivity associated with a
are not interchangeable with other preparations of botulinum toxin products and, therefore, Neurologic Condition
units of biological activity of BOTOX cannot be compared to nor converted into units of any Patients with compromised respiratory status treated with BOTOX for upper limb spasticity
other botulinum toxin products assessed with any other specific assay method [see Dosage should be monitored closely. In a double-blind, placebo-controlled, parallel group study
and Administration (2.1), Description (11)]. in patients with stable reduced pulmonary function (defined as FEV1 40-80% of predicted
5.2 Spread of Toxin Effect value and FEV1/FVC ≤ 0.75), the event rate in change of Forced Vital Capacity ≥15% or
Postmarketing safety data from BOTOX and other approved botulinum toxins suggest that ≥20% was generally greater in patients treated with BOTOX than in patients treated with
botulinum toxin effects may, in some cases, be observed beyond the site of local injection. placebo (see Table 4).
The symptoms are consistent with the mechanism of action of botulinum toxin and may Table 4: Event rate per patient treatment cycle among patients with reduced lung
include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, function who experienced at least a 15% or 20% decrease in forced vital capacity
dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been from baseline at Week 1, 6, 12 post-injection with up to two treatment cycles with
reported hours to weeks after injection. Swallowing and breathing difficulties can be life BOTOX or placebo
threatening and there have been reports of death related to spread of toxin effects. The
BOTOX BOTOX
risk of symptoms is probably greatest in children treated for spasticity but symptoms can Placebo
360 Units 240 Units
also occur in adults treated for spasticity and other conditions, and particularly in those
patients who have an underlying condition that would predispose them to these symptoms. ≥15% ≥20% ≥15% ≥20% ≥15% ≥20%
In unapproved uses, including spasticity in children, and in approved indications, symptoms
consistent with spread of toxin effect have been reported at doses comparable to or lower Week 1 4% 0% 3% 0% 7% 3%
than doses used to treat cervical dystonia and upper limb spasticity. Patients or caregivers Week 6 7% 4% 4% 2% 2% 2%
should be advised to seek immediate medical care if swallowing, speech or respiratory
disorders occur. Week 12 10% 5% 2% 1% 4% 1%
No definitive serious adverse event reports of distant spread of toxin effect associated with Differences from placebo were not statistically significant
dermatologic use of BOTOX/BOTOX Cosmetic at the labeled dose of 20 Units (for glabellar In patients with reduced lung function, upper respiratory tract infections were also reported
lines) or 100 Units (for severe primary axillary hyperhidrosis) have been reported. more frequently as adverse reactions in patients treated with BOTOX than in patients
No definitive serious adverse event reports of distant spread of toxin effect associated with treated with placebo [see Warnings and Precautions (5.10)].
BOTOX for blepharospasm at the recommended dose (30 Units and below), strabismus, or
for chronic migraine at the labeled doses have been reported.
In an ongoing double-blind, placebo-controlled, parallel group study in adult patients with Table 6: Proportion of Patients Catheterizing for Urinary Retention and Duration of
detrusor overactivity associated with a neurologic condition and restrictive lung disease of Catheterization following an injection in double-blind, placebo-controlled clinical
neuromuscular etiology [defined as FVC 50-80% of predicted value in patients with spinal trials in OAB
cord injury between C5 and C8, or MS] the event rate in change of Forced Vital Capacity
≥15% or ≥20% was generally greater in patients treated with BOTOX than in patients BOTOX
Placebo
treated with placebo (see Table 5). Timepoint 100 Units
(N=542)
(N=552)
Table 5: Number and percent of patients experiencing at least a 15% or 20% decrease
in FVC from baseline at Week 2, 6, 12 post-injection with BOTOX or placebo Proportion of Patients Catheterizing for Urinary Retention

BOTOX At any time during complete

Placebo 6.5% (n=36) 0.4% (n=2)
200 Units treatment cycle

≥15% ≥20% ≥15% ≥20% Duration of Catheterization for Urinary Retention (Days)

Week 2 0/12 (0%) 0/12 (0%) 1/11 (9%) 0/11 (0%) Median 63 11

Week 6 2/11 (18%) 1/11 (9%) 0/11 (0%) 0/11 (0%) Min, Max 1, 214 3, 18

Week 12 0/11 (0%) 0/11 (0%) 0/6 (0%) 0/6 (0%) Patients with diabetes mellitus treated with BOTOX were more likely to develop urinary
retention than those without diabetes, as shown in Table 7.
5.8 Corneal Exposure and Ulceration in Patients Treated with BOTOX
Table 7. Proportion of Patients Experiencing Urinary Retention following an injection
for Blepharospasm
in double-blind, placebo-controlled clinical trials in OAB according to history of
Reduced blinking from BOTOX injection of the orbicularis muscle can lead to corneal
Diabetes Mellitus
exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII
nerve disorders. Vigorous treatment of any epithelial defect should be employed. This may Patients with Diabetes Patients without Diabetes
require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by
patching or other means. BOTOX BOTOX
Placebo Placebo
100 Units 100 Units
5.9 Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus (N=69) (N=516)
(N=81) (N=526)
During the administration of BOTOX for the treatment of strabismus, retrobulbar
hemorrhages sufficient to compromise retinal circulation have occurred. It is recommended Urinary retention 12.3% (n=10) 0 6.3% (n=33) 0.6% (n=3)
that appropriate instruments to decompress the orbit be accessible.
Detrusor Overactivity associated with a Neurologic Condition
5.10 Bronchitis and Upper Respiratory Tract Infections in Patients Treated In double-blind, placebo-controlled trials in patients with detrusor overactivity associated
for Spasticity with a neurologic condition, the proportion of subjects who were not using clean intermittent
Bronchitis was reported more frequently as an adverse reaction in patients treated for catheterization (CIC) prior to injection and who subsequently required catheterization for
upper limb spasticity with BOTOX (3% at 251 Units-360 Units total dose), compared to urinary retention following treatment with BOTOX or placebo is shown in Table 8. The
placebo (1%). In patients with reduced lung function treated for upper limb spasticity, duration of post-injection catheterization for those who developed urinary retention is
upper respiratory tract infections were also reported more frequently as adverse reactions also shown.
in patients treated with BOTOX (11% at 360 Units total dose; 8% at 240 Units total dose)
compared to placebo (6%). Table 8: Proportion of Patients not using CIC at baseline and then Catheterizing for
Urinary Retention and Duration of Catheterization following an injection in double-
5.11 Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity associated blind, placebo-controlled clinical trials
with a Neurologic Condition
Autonomic dysreflexia associated with intradetrusor injections of BOTOX could occur in BOTOX
Placebo
patients treated for detrusor overactivity associated with a neurologic condition and may Timepoint 200 Units
(N=104)
require prompt medical therapy. In clinical trials, the incidence of autonomic dysreflexia (N=108)
was greater in patients treated with BOTOX 200 Units compared with placebo (1.5% versus Proportion of Patients Catheterizing for Urinary Retention
0.4%, respectively).
5.12 Urinary Tract Infections in Patients with Overactive Bladder At any time during complete
30.6% (n=33) 6.7% (n=7)
BOTOX increases the incidence of urinary tract infection [see Adverse Reactions (6.1)]. treatment cycle
Clinical trials for overactive bladder excluded patients with more than 2 UTIs in the past Duration of Catheterization for Urinary Retention (Days)
6 months and those taking antibiotics chronically due to recurrent UTIs. Use of BOTOX for
the treatment of overactive bladder in such patients and in patients with multiple recurrent Median 289 358
UTIs during treatment should only be considered when the benefit is likely to outweigh the Min, Max 1, 530 2, 379
potential risk.
5.13 Urinary Retention in Patients Treated for Bladder Dysfunction Among patients not using CIC at baseline, those with MS were more likely to require CIC
Due to the risk of urinary retention, treat only patients who are willing and able to initiate post-injection than those with SCI (see Table 9).
catheterization post-treatment, if required, for urinary retention. Table 9: Proportion of Patients by Etiology (MS and SCI) not using CIC at baseline
In patients who are not catheterizing, post-void residual (PVR) urine volume should be and then Catheterizing for Urinary Retention following an injection in double-blind,
assessed within 2 weeks post-treatment and periodically as medically appropriate up to placebo-controlled clinical trials
12 weeks, particularly in patients with multiple sclerosis or diabetes mellitus. Depending MS SCI
on patient symptoms, institute catheterization if PVR urine volume exceeds 200 mL and
continue until PVR falls below 200 mL. Instruct patients to contact their physician if they Timepoint BOTOX BOTOX
Placebo Placebo
experience difficulty in voiding as catheterization may be required. 200 Units 200 Units
(N=88) (N=16)
(N=86) (N=22)
The incidence and duration of urinary retention is described below for patients with
overactive bladder and detrusor overactivity associated with a neurologic condition who At any time during
31% (n=27) 5% (n=4) 27% (n=6) 19% (n=3)
received BOTOX or placebo injections. complete treatment cycle
Overactive Bladder
5.14 Human Albumin and Transmission of Viral Diseases
In double-blind, placebo-controlled trials in patients with OAB, the proportion of subjects
This product contains albumin, a derivative of human blood. Based on effective donor
who initiated clean intermittent catheterization (CIC) for urinary retention following
screening and product manufacturing processes, it carries an extremely remote risk for
treatment with BOTOX or placebo is shown in Table 6. The duration of post-injection
transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob
catheterization for those who developed urinary retention is also shown.
disease (CJD) is also considered extremely remote. No cases of transmission of viral
diseases or CJD have ever been reported for albumin.
6 ADVERSE REACTIONS
The following adverse reactions to BOTOX (onabotulinumtoxinA) for injection are discussed
in greater detail in other sections of the labeling:
• Spread of Toxin Effects [see Warnings and Precautions (5.2)]
• Hypersensitivity [see Contraindications (4.1) and Warnings and Precautions (5.4)]
• Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.6)]
• Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity [see
Warnings and Precautions (5.10)]
• Urinary Retention in Patients Treated for Bladder Dysfunction [see Warnings and
Precautions (5.13)]
6.1 Clinical Trials Experience Chronic Migraine
Because clinical trials are conducted under widely varying conditions, the adverse reaction In double-blind, placebo-controlled chronic migraine efficacy trials (Study 1 and Study 2),
rates observed in the clinical trials of a drug cannot be directly compared to rates in the the discontinuation rate was 12% in the BOTOX treated group and 10% in the placebo-
clinical trials of another drug and may not reflect the rates observed in clinical practice. treated group. Discontinuations due to an adverse event were 4% in the BOTOX group and
BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, 1% in the placebo group. The most frequent adverse events leading to discontinuation in
but with different labeled Indications and Usage. Therefore, adverse reactions observed with the BOTOX group were neck pain, headache, worsening migraine, muscular weakness and
the use of BOTOX Cosmetic also have the potential to be observed with the use of BOTOX. eyelid ptosis.
In general, adverse reactions occur within the first week following injection of BOTOX The most frequently reported adverse reactions following injection of BOTOX for chronic
and while generally transient, may have a duration of several months or longer. Localized migraine appear in Table 13.
pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising Table 13: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and More
may be associated with the injection. Needle-related pain and/or anxiety may result in Frequent than in Placebo-treated Patients in Two Chronic Migraine Double-blind,
vasovagal responses (including e.g., syncope, hypotension), which may require appropriate Placebo-controlled Clinical Trials
medical therapy.
BOTOX
Local weakness of the injected muscle(s) represents the expected pharmacological action Placebo
Adverse Reactions by System Organ Class 155 Units-195 Units
of botulinum toxin. However, weakness of nearby muscles may also occur due to spread of (N=692)
(N=687)
toxin [see Warnings and Precautions (5.2)].
Nervous system disorders
Overactive Bladder
Table 10 presents the most frequently reported adverse reactions in double-blind, placebo-  Headache 32 (5%) 22 (3%)
controlled clinical trials for overactive bladder occurring within 12 weeks of the first  Migraine 26 (4%) 18 (3%)
BOTOX treatment.   Facial paresis 15 (2%) 0 (0%)
Table 10: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and More Eye disorders
Often than in Placebo-treated Patients Within the First 12 Weeks after Intradetrusor   Eyelid ptosis 25 (4%) 2 (<1%)
Injection, in Double-blind, Placebo-controlled Clinical Trials in Patients with OAB
Infections and Infestations
BOTOX  Bronchitis 17 (3%) 11 (2%)
Placebo
Adverse Reactions 100 Units
(N=542) Musculoskeletal and connective tissue disorders
(N=552)
  Neck pain 60 (9%) 19 (3%)
Urinary tract infection 99 (18%) 30 (6%)
  Musculoskeletal stiffness 25 (4%) 6 (1%)
Dysuria 50 (9%) 36 (7%)
  Muscular weakness 24 (4%) 2 (<1%)
Urinary retention 31 (6%) 2 (0%)
 Myalgia 21 (3%) 6 (1%)
Bacteriuria 24 (4%) 11 (2%)
  Musculoskeletal pain 18 (3%) 10 (1%)
Residual urine volume* 17 (3%) 1 (0%)
  Muscle spasms 13 (2%) 6 (1%)
* Elevated PVR not requiring catheterization. Catheterization was required for PVR ≥350 mL General disorders and administration site conditions
regardless of symptoms, and for PVR ≥200 mL to <350 mL with symptoms (e.g.,   Injection site pain 23 (3%) 14 (2%)
voiding difficulty).
Vascular Disorders
A higher incidence of urinary tract infection was observed in patients with diabetes mellitus
treated with BOTOX 100 Units and placebo than in patients without diabetes, as shown in  Hypertension 11 (2%) 7 (1%)
Table 11. Other adverse reactions that occurred more frequently in the BOTOX group compared to
Table 11: Proportion of Patients Experiencing Urinary Tract Infection following an the placebo group at a frequency less than 1% and potentially BOTOX related include:
Injection in Double-blind, Placebo-controlled Clinical Trials in OAB according to vertigo, dry eye, eyelid edema, dysphagia, eye infection, and jaw pain. Severe worsening of
history of Diabetes Mellitus migraine requiring hospitalization occurred in approximately 1% of BOTOX treated patients
in Study 1 and Study 2, usually within the first week after treatment, compared to 0.3% of
Patients with Diabetes Patients without Diabetes
placebo-treated patients.
BOTOX BOTOX Upper Limb Spasticity
Placebo Placebo
100 Units 100 Units The most frequently reported adverse reactions following injection of BOTOX for adult
(N=69) (N=516)
(N=81) (N=526) spasticity appear in Table 14.
Urinary tract infection (UTI) 25 (31%) 8 (12%) 135 (26%) 51 (10%) Table 14: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and More
Frequent than in Placebo-treated Patients in Adult Spasticity Double-blind, Placebo-
The incidence of UTI increased in patients who experienced a maximum post-void residual controlled Clinical Trials
(PVR) urine volume ≥200 mL following BOTOX injection compared to those with a maximum
PVR <200 mL following BOTOX injection, 44% versus 23%, respectively. No change was BOTOX BOTOX
BOTOX
observed in the overall safety profile with repeat dosing during an open-label, uncontrolled Adverse Reactions by 251 Units- 150 Units- Placebo
<150 Units
extension trial. System Organ Class 360 Units 250 Units (N=182)
(N=54)
(N=115) (N=188)
Detrusor Overactivity associated with a Neurologic Condition
Table 12 presents the most frequently reported adverse reactions in double-blind, placebo- Gastrointestinal disorder
controlled studies within 12 weeks of injection for detrusor overactivity associated with a  Nausea 3 (3%) 3 (2%) 1 (2%) 1 (1%)
neurologic condition.
General disorders and
Table 12: Adverse Reactions Reported by ≥2% of BOTOX treated Patients and administration site conditions
More Frequent than in Placebo-treated Patients Within the First 12 Weeks after
 Fatigue 4 (3%) 4 (2%) 1 (2%) 0
Intradetrusor Injection in Double-blind, Placebo-controlled Clinical Trials
Infections and infestations
BOTOX
Placebo  Bronchitis 4 (3%) 4 (2%) 0 2 (1%)
Adverse Reactions 200 Units
(N=272)
(N=262) Musculoskeletal and
Urinary tract infection 64 (24%) 47 (17%) connective tissue disorders
Urinary retention 45 (17%) 8 (3%)   Pain in extremity 7 (6%) 10 (5%) 5 (9%) 8 (4%)
Hematuria 10 (4%) 8 (3%)   Muscular weakness 0 7 (4%) 1 (2%) 2 (1%)

The following adverse reactions with BOTOX 200 Units were reported at any time following Twenty two adult patients, enrolled in double-blind placebo controlled studies, received
initial injection and prior to re-injection or study exit (median duration of 44 weeks of 400 Units or higher of BOTOX for treatment of upper limb spasticity. In addition, 44 adults
exposure): urinary tract infections (49%), urinary retention (17%), constipation (4%), received 400 Units of BOTOX or higher for four consecutive treatments over approximately
muscular weakness (4%), dysuria (4%), fall (3%), gait disturbance (3%), and muscle one year for treatment of upper limb spasticity. The type and frequency of adverse reactions
spasm (2%). observed in patients treated with 400 Units of BOTOX were similar to those reported in
patients treated for upper limb spasticity with 360 Units of BOTOX.
In the MS patients enrolled in the double-blind, placebo-controlled trials, the MS
exacerbation annualized rate (i.e., number of MS exacerbation events per patient-year)
was 0.23 for BOTOX and 0.20 for placebo.
No change was observed in the overall safety profile with repeat dosing.
Cervical Dystonia 6.3 Post-Marketing Experience
In cervical dystonia patients evaluated for safety in double-blind and open-label studies The following adverse reactions have been identified during post-approval use of BOTOX.
following injection of BOTOX, the most frequently reported adverse reactions were Because these reactions are reported voluntarily from a population of uncertain size, it is
dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%). not always possible to reliably estimate their frequency or establish a causal relationship
Other events reported in 2-10% of patients in any one study in decreasing order of to drug exposure. These reactions include: abdominal pain; alopecia, including madarosis;
incidence include: increased cough, flu syndrome, back pain, rhinitis, dizziness, hypertonia, anorexia; brachial plexopathy; denervation/muscle atrophy; diarrhea; hyperhidrosis;
soreness at injection site, asthenia, oral dryness, speech disorder, fever, nausea, and hypoacusis; hypoaesthesia; malaise; paresthesia; peripheral neuropathy; radiculopathy;
drowsiness. Stiffness, numbness, diplopia, ptosis, and dyspnea have been reported. erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption; strabismus;
tinnitus; and visual disturbances.
Dysphagia and symptomatic general weakness may be attributable to an extension of the
pharmacology of BOTOX resulting from the spread of the toxin outside the injected muscles There have been spontaneous reports of death, sometimes associated with dysphagia,
[see Warnings and Precautions (5.2, 5.6)]. pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum
toxin [see Warnings and Precautions (5.4, 5.6)].
The most common severe adverse reaction associated with the use of BOTOX injection in
patients with cervical dystonia is dysphagia with about 20% of these cases also reporting There have also been reports of adverse events involving the cardiovascular system,
dyspnea [see Warnings and Precautions (5.2, 5.6)]. Most dysphagia is reported as mild or including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these
moderate in severity. However, it may be associated with more severe signs and symptoms patients had risk factors including cardiovascular disease. The exact relationship of these
[see Warnings and Precautions (5.6)]. events to the botulinum toxin injection has not been established.
Additionally, reports in the literature include a case of a female patient who developed New onset or recurrent seizures have also been reported, typically in patients who are
brachial plexopathy two days after injection of 120 Units of BOTOX for the treatment predisposed to experiencing these events. The exact relationship of these events to the
of cervical dystonia, and reports of dysphonia in patients who have been treated for botulinum toxin injection has not been established.
cervical dystonia. 7 DRUG INTERACTIONS
Primary Axillary Hyperhidrosis 7.1 Aminoglycosides and Other Agents Interfering with
The most frequently reported adverse reactions (3-10% of adult patients) following injection Neuromuscular Transmission
of BOTOX in double-blind studies included injection site pain and hemorrhage, non-axillary Co-administration of BOTOX and aminoglycosides or other agents interfering with
sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, neuromuscular transmission (e.g., curare-like compounds) should only be performed with
and anxiety. caution as the effect of the toxin may be potentiated.
The data reflect 346 patients exposed to BOTOX 50 Units and 110 patients exposed to 7.2 Anticholinergic Drugs
BOTOX 75 Units in each axilla. Use of anticholinergic drugs after administration of BOTOX may potentiate systemic
anticholinergic effects.
Blepharospasm
In a study of blepharospasm patients who received an average dose per eye of 33 Units 7.3 Other Botulinum Neurotoxin Products
(injected at 3 to 5 sites) of the currently manufactured BOTOX, the most frequently The effect of administering different botulinum neurotoxin products at the same time or
reported adverse reactions were ptosis (21%), superficial punctate keratitis (6%), and within several months of each other is unknown. Excessive neuromuscular weakness may
eye dryness (6%). be exacerbated by administration of another botulinum toxin prior to the resolution of the
effects of a previously administered botulinum toxin.
Other events reported in prior clinical studies in decreasing order of incidence include:
irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia, entropion, 7.4 Muscle Relaxants
diffuse skin rash, and local swelling of the eyelid skin lasting for several days following Excessive weakness may also be exaggerated by administration of a muscle relaxant before
eyelid injection. or after administration of BOTOX.
In two cases of VII nerve disorder, reduced blinking from BOTOX injection of the orbicularis 8 USE IN SPECIFIC POPULATIONS
muscle led to serious corneal exposure, persistent epithelial defect, corneal ulceration and a 8.1 Pregnancy
case of corneal perforation. Focal facial paralysis, syncope, and exacerbation of myasthenia Pregnancy Category C.
gravis have also been reported after treatment of blepharospasm. There are no adequate and well-controlled studies in pregnant women. BOTOX should be
Strabismus used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Extraocular muscles adjacent to the injection site can be affected, causing vertical deviation, When BOTOX (4, 8, or 16 Units/kg) was administered intramuscularly to pregnant mice or
especially with higher doses of BOTOX. The incidence rates of these adverse effects in rats two times during the period of organogenesis (on gestation days 5 and 13), reductions
2058 adults who received a total of 3650 injections for horizontal strabismus was 17%. in fetal body weight and decreased fetal skeletal ossification were observed at the two
The incidence of ptosis has been reported to be dependent on the location of the injected highest doses. The no-effect dose for developmental toxicity in these studies (4 Units/kg) is
muscles, 1% after inferior rectus injections, 16% after horizontal rectus injections and 38% approximately 0.7 times the average high human dose for upper limb spasticity of 360 Units
after superior rectus injections. on a body weight basis (Units/kg).
In a series of 5587 injections, retrobulbar hemorrhage occurred in 0.3% of cases. When BOTOX was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4,
6.2 Immunogenicity or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or 0.5 Units/kg) daily during the period of
As with all therapeutic proteins, there is a potential for immunogenicity. Formation of organogenesis (total of 12 doses in rats, 13 doses in rabbits), reduced fetal body weights
neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX and decreased fetal skeletal ossification were observed at the two highest doses in rats and
treatment by inactivating the biological activity of the toxin. at the highest dose in rabbits. These doses were also associated with significant maternal
toxicity, including abortions, early deliveries, and maternal death. The developmental no-
In a long term, open-label study evaluating 326 cervical dystonia patients treated for an effect doses in these studies of 1 Unit/kg in rats and 0.25 Units/kg in rabbits are less than
average of 9 treatment sessions with the current formulation of BOTOX, 4 (1.2%) patients the average high human dose based on Units/kg.
had positive antibody tests. All 4 of these patients responded to BOTOX therapy at the time
of the positive antibody test. However, 3 of these patients developed clinical resistance after When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three
subsequent treatment, while the fourth patient continued to respond to BOTOX therapy for different periods of development (prior to implantation, implantation, or organogenesis), no
the remainder of the study. adverse effects on fetal development were observed. The developmental no-effect level
for a single maternal dose in rats (16 Units/kg) is approximately 3 times the average high
One patient among the 445 hyperhidrosis patients (0.2%), two patients among the 380 human dose based on Units/kg.
adult upper limb spasticity patients (0.5%), no patients among 406 migraine patients, no
patients among 615 overactive bladder patients, and no patients among 475 detrusor 8.3 Nursing Mothers
overactivity associated with a neurologic condition patients with analyzed specimens It is not known whether BOTOX is excreted in human milk. Because many drugs are
developed the presence of neutralizing antibodies. excreted in human milk, caution should be exercised when BOTOX is administered to a
nursing woman.
The data reflect the patients whose test results were considered positive or negative for
neutralizing activity to BOTOX in a mouse protection assay. The results of these tests are 8.4 Pediatric Use
highly dependent on the sensitivity and specificity of the assay. Additionally, the observed Bladder Dysfunction
incidence of antibody (including neutralizing antibody) positivity in an assay may be Safety and effectiveness in patients below the age of 18 years have not been established.
influenced by several factors including assay methodology, sample handling, timing of Prophylaxis of Headaches in Chronic Migraine
sample collection, concomitant medications, and underlying disease. For these reasons, Safety and effectiveness in patients below the age of 18 years have not been established.
comparison of the incidence of neutralizing activity to BOTOX with the incidence of Spasticity
antibodies to other products may be misleading. Safety and effectiveness in patients below the age of 18 years have not been established.
The critical factors for neutralizing antibody formation have not been well characterized. The Axillary Hyperhidrosis
results from some studies suggest that BOTOX injections at more frequent intervals or at Safety and effectiveness in patients below the age of 18 years have not been established.
higher doses may lead to greater incidence of antibody formation. The potential for antibody
formation may be minimized by injecting with the lowest effective dose given at the longest Cervical Dystonia
feasible intervals between injections. Safety and effectiveness in pediatric patients below the age of 16 years have not
been established.
Blepharospasm and Strabismus Each vial of BOTOX contains either 100 Units of Clostridium botulinum type A neurotoxin
Safety and effectiveness in pediatric patients below the age of 12 years have not complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride; or 200 Units of
been established. Clostridium botulinum type A neurotoxin complex, 1 mg of Albumin Human, and 1.8 mg
8.5 Geriatric Use of sodium chloride in a sterile, vacuum-dried form without a preservative.
Overall, with the exception of Overactive Bladder (see below), clinical studies of BOTOX 12 CLINICAL PHARMACOLOGY
did not include sufficient numbers of subjects aged 65 and over to determine whether 12.1 Mechanism of Action
they respond differently from younger subjects. Other reported clinical experience has not BOTOX blocks neuromuscular transmission by binding to acceptor sites on motor or
identified differences in responses between the elderly and younger patients. There were sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of
too few patients over the age of 75 to enable any comparisons. In general, dose selection acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral
for an elderly patient should be cautious, usually starting at the low end of the dosing range, to the successful docking and release of acetylcholine from vesicles situated within nerve
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of endings. When injected intramuscularly at therapeutic doses, BOTOX produces partial
concomitant disease or other drug therapy. chemical denervation of the muscle resulting in a localized reduction in muscle activity.
Overactive Bladder In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional
Of 1242 overactive bladder patients in placebo-controlled clinical studies of BOTOX, 41.4% acetylcholine receptors may develop. There is evidence that reinnervation of the muscle
(n=514) were 65 years of age or older, and 14.7% (n=182) were 75 years of age or older. may occur, thus slowly reversing muscle denervation produced by BOTOX.
Adverse reactions of UTI and urinary retention were more common in patients 65 years of When injected intradermally, BOTOX produces temporary chemical denervation of the sweat
age or older in both placebo and BOTOX groups compared to younger patients (see Table gland resulting in local reduction in sweating.
15). Otherwise, there were no overall differences in the safety profile following BOTOX
Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity
treatment between patients aged 65 years and older compared to younger patients in
via inhibition of acetylcholine release.
these studies.
12.3 Pharmacokinetics
Table 15. Incidence of Urinary Tract Infection and Urinary Retention according to Age
Using currently available analytical technology, it is not possible to detect BOTOX in the
Group during First Placebo-controlled Treatment, Placebo-controlled Clinical Trials in
peripheral blood following intramuscular injection at the recommended doses.
Patients with OAB
13 NONCLINICAL TOXICOLOGY
<65 Years 65 to 74 Years ≥75 Years 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
BOTOX BOTOX BOTOX Carcinogenesis
Adverse Placebo Placebo Placebo Long term studies in animals have not been performed to evaluate the carcinogenic
100 Units 100 Units 100 Units
Reactions (N=348) (N=151) (N=86) potential of BOTOX.
(N=344) (N=169) (N=94)
Urinary tract Mutagenesis
infection 73 (21%) 23 (7%) 51 (30%) 20 (13%) 36 (38%) 16 (19%) BOTOX was negative in a battery of in vitro (microbial reverse mutation assay, mammalian
cell mutation assay, and chromosomal aberration assay) and in vivo (micronucleus assay)
Urinary retention 21 (6%) 2 (0.6%) 14 (8%) 0 (0%) 8 (9%) 1 (1%) genetic toxicologic assays.
Observed effectiveness was comparable between these age groups in placebo-controlled Impairment of Fertility
clinical studies. In fertility studies of BOTOX (4, 8, or 16 Units/kg) in which either male or female rats were
injected intramuscularly prior to mating and on the day of mating (3 doses, 2 weeks apart
10 OVERDOSAGE for males, 2 doses, 2 weeks apart for females) to untreated animals, reduced fertility was
Excessive doses of BOTOX (onabotulinumtoxinA) for injection may be expected to produce observed in males at the intermediate and high doses and in females at the high dose. The
neuromuscular weakness with a variety of symptoms. no-effect doses for reproductive toxicity (4 Units/kg in males, 8 Units/kg in females) are
Symptoms of overdose are likely not to be present immediately following injection. Should approximately equal to the average high human dose for upper limb spasticity of 360 Units
accidental injection or oral ingestion occur or overdose be suspected, the person should on a body weight basis (Units/kg).
be medically supervised for several weeks for signs and symptoms of systemic muscular 13.2 Animal Toxicology
weakness which could be local, or distant from the site of injection [see Boxed Warning In a study to evaluate inadvertent peribladder administration, bladder stones were observed
and Warnings and Precautions (5.2, 5.6)]. These patients should be considered for further in 1 of 4 male monkeys that were injected with a total of 6.8 Units/kg divided into the
medical evaluation and appropriate medical therapy immediately instituted, which may prostatic urethra and proximal rectum (single administration). No bladder stones were
include hospitalization. observed in male or female monkeys following injection of up to 36 Units/kg (~12X the
If the musculature of the oropharynx and esophagus are affected, aspiration may occur highest human bladder dose) directly to the bladder as either single or 4 repeat dose
which may lead to development of aspiration pneumonia. If the respiratory muscles become injections or in female rats for single injections up to 100 Units/kg (~33X the highest human
paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary bladder dose).
until recovery takes place. Supportive care could involve the need for a tracheostomy 14 CLINICAL STUDIES
and/or prolonged mechanical ventilation, in addition to other general supportive care. 14.1 Overactive Bladder (OAB)
In the event of overdose, antitoxin raised against botulinum toxin is available from the Two double-blind, placebo-controlled, randomized, multi-center, 24-week clinical studies
Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin were conducted in patients with OAB with symptoms of urge urinary incontinence,
will not reverse any botulinum toxin-induced effects already apparent by the time of urgency, and frequency (Studies OAB-1 and OAB-2). Patients needed to have at least 3
antitoxin administration. In the event of suspected or actual cases of botulinum toxin urinary urgency incontinence episodes and at least 24 micturitions in 3 days to enter the
poisoning, please contact your local or state Health Department to process a request studies. A total of 1105 patients, whose symptoms had not been adequately managed with
for antitoxin through the CDC. If you do not receive a response within 30 minutes, anticholinergic therapy (inadequate response or intolerable side effects), were randomized
please contact the CDC directly at 1-770-488-7100. More information can be obtained to receive either 100 Units of BOTOX (n=557), or placebo (n=548). Patients received 20
at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm. injections of study drug (5 units of BOTOX or placebo) spaced approximately 1 cm apart into
11 DESCRIPTION the detrusor muscle.
BOTOX (onabotulinumtoxinA) for injection is a sterile, vacuum-dried purified botulinum In both studies, significant improvements compared to placebo in the primary efficacy
toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A, variable of change from baseline in daily frequency of urinary incontinence episodes
and intended for intramuscular, intradetrusor and intradermal use. It is purified from the were observed for BOTOX 100 Units at the primary time point of week 12. Significant
culture solution by dialysis and a series of acid precipitations to a complex consisting of improvements compared to placebo were also observed for the secondary efficacy variables
the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium of daily frequency of micturition episodes and volume voided per micturition. These primary
chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to and secondary variables are shown in Tables 16 and 17, and Figures 4 and 5.
filling and vacuum-drying.
The primary release procedure for BOTOX uses a cell-based potency assay to determine
the potency relative to a reference standard. The assay is specific to Allergan’s products
BOTOX and BOTOX Cosmetic. One Unit of BOTOX corresponds to the calculated median
intraperitoneal lethal dose (LD50) in mice. Due to specific details of this assay such as the
vehicle, dilution scheme, and laboratory protocols, Units of biological activity of BOTOX
cannot be compared to nor converted into Units of any other botulinum toxin or any
toxin assessed with any other specific assay method. The specific activity of BOTOX is
approximately 20 Units/nanogram of neurotoxin protein complex.
Table 16: Baseline and Change from Baseline in Urinary Incontinence Episode Figure 4: Mean Change from Baseline in Daily Frequency of Urinary Incontinence
Frequency, Micturition Episode Frequency and Volume Voided Per Micturition, Episodes following intradetrusor injection in Study OAB-1
Study OAB-1
0 Treatment
BOTOX
Placebo Treatment Placebo
100 Units p-value

Mean Change From Baseline (± SE)

(N=272) Difference -0.5 (n = 272)
(N=278) BOTOX®
-1 100 U (n = 278)
Daily Frequency of Urinary

Episodes per Day:

Incontinence Episodesa -1.5 **: p < 0.001
  Mean Baseline 5.5 5.1
-2
  Mean Change* at Week 2 -2.6 -1.0 -1.6
-2.5 **
  Mean Change* at Week 6 -2.8 -1.0 -1.8
  Mean Change* at Week 12** -2.5 -0.9 -1.6 <0.001 -3
(-2.1, -1.2)
-3.5
Daily Frequency of Micturition 0 2 6 12
Episodesb
Weeks Post-Treatment
  Mean Baseline 12.0 11.2
  Mean Change† at Week 12** -1.9 -0.9 -1.0 <0.001
(-1.5, -0.6) Figure 5: Mean Change from Baseline in Daily Frequency of Urinary Incontinence
Episodes following intradetrusor injection in Study OAB-2
Volume Voided per Micturition b

(mL) 0 Treatment
  Mean Baseline 156 161 Placebo

Mean Change From Baseline (± SE)

-0.5 (n = 269)
  Mean Change at Week 12**
†
38 8 30 <0.001 BOTOX®
(17, 43) -1 100 U (n = 275)

Episodes per Day:

* Least squares (LS) mean change, treatment difference and p-value are based on an -1.5 **: p < 0.001
ANCOVA model with baseline value as covariate and treatment group and investigator as
factors. Last observation carried forward (LOCF) values were used to analyze the primary -2
efficacy variable.
†
LS mean change, treatment difference and p-value are based on an ANCOVA model with -2.5
**
baseline value as covariate and stratification factor, treatment group and investigator
-3
as factors.
** Primary timepoint -3.5
a
Primary variable 0 2 6 12
b
Secondary variable
Table 17: Baseline and Change from Baseline in Urinary Incontinence Episode Weeks Post-Treatment
Frequency, Micturition Episode Frequency and Volume Voided Per Micturition,
Study OAB-2
The median duration of response in Study OAB-1 and OAB-2, based on patient qualification
BOTOX for re-treatment, was 19-24 weeks for the BOTOX 100 Unit dose group compared to 13
Placebo Treatment
100 Units p-value weeks for placebo. To qualify for re-treatment, at least 12 weeks must have passed since
(N=269) Difference
(N=275) the prior treatment, post-void residual urine volume must have been less than 200 mL and
Daily Frequency of Urinary patients must have reported at least 2 urinary incontinence episodes over 3 days.
Incontinence Episodesa 14.2 Detrusor Overactivity associated with a Neurologic Condition
  Mean Baseline 5.5 5.7 Two double-blind, placebo-controlled, randomized, multi-center clinical studies were
conducted in patients with urinary incontinence due to detrusor overactivity associated
  Mean Change* at Week 2 -2.7 -1.1 -1.6 with a neurologic condition who were either spontaneously voiding or using catheterization
  Mean Change* at Week 6 -3.1 -1.3 -1.8 (Studies NDO-1 and NDO-2). A total of 691 spinal cord injury (T1 or below) or multiple
sclerosis patients, who had an inadequate response to or were intolerant of at least one
  Mean Change* at Week 12** -3.0 -1.1 -1.9 <0.001 anticholinergic medication, were enrolled. These patients were randomized to receive either
(-2.5, -1.4) 200 Units of BOTOX (n=227), 300 Units of BOTOX (n=223), or placebo (n=241).
Daily Frequency of Micturition In both studies, significant improvements compared to placebo in the primary efficacy
Episodesb variable of change from baseline in weekly frequency of incontinence episodes were
observed for BOTOX (200 Units) at the primary efficacy time point at week 6. Increases in
  Mean Baseline 12.0 11.8 maximum cystometric capacity and reductions in maximum detrusor pressure during the
  Mean Change† at Week 12** -2.3 -0.6 -1.7 <0.001 first involuntary detrusor contraction were also observed. These primary and secondary
(-2.2, -1.3) endpoints are shown in Tables 18 and 19, and Figures 6 and 7.
Volume Voided per Micturitionb No additional benefit of BOTOX 300 Units over 200 Units was demonstrated.
(mL)
  Mean Baseline 144 153
  Mean Change† at Week 12** 40 10 31 <0.001
(20, 41)

* LS mean change, treatment difference and p-value are based on an ANCOVA model with
baseline value as covariate and treatment group and investigator as factors. LOCF values
were used to analyze the primary efficacy variable.
†
LS mean change, treatment difference and p-value are based on an ANCOVA model with
baseline value as covariate and stratification factor, treatment group and investigator
as factors.
** Primary timepoint
a
Primary variable
b
Secondary variable
Table 18: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode Figure 6: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence
Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during Episodes During Treatment Cycle 1 in Study NDO-1
First Involuntary Detrusor Contraction (cmH2O) Study NDO-1
0
BOTOX Placebo Treatment Treatment
p-value*

Mean Change from Baseline (± Std Err)

200 Units Difference* Placebo
(n = 146)
-5
Weekly Frequency of Urinary BOTOX® 200 U
Incontinence Episodesa (n = 134)

Episodes/Week:
-10
 N 134 146 ** p < 0.001
  Mean Baseline 32.3 28.3
-15
  Mean Change* at Week 2 -15.3 -10.0 -5.3 —
**
-9.2 -20
  Mean Change* at Week 6** -19.9 -10.6 p<0.001
(-13.1, -5.3)
  Mean Change* at Week 12 -19.8 -8.8 -11.0 — -25

Maximum Cystometric 0 2 6 12
Capacityb (mL) Weeks Post-Treatment

 N 123 129
  Mean Baseline 253.8 259.1 Figure 7: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence
  Mean Change* at Week 6** 135.9 12.1 123.9 p<0.001 Episodes During Treatment Cycle 1 in Study NDO-2
(89.1, 158.7)
0
Maximum Detrusor Pressure Treatment

Mean Change from Baseline (± Std Err)

during First Involuntary Placebo
(n = 91)
Detrusor Contractionb (cmH2O) -5
BOTOX® 200 U
 N 41 103 (n = 91)

Episodes/Week:
-10
  Mean Baseline 63.1 57.4 * p < 0.05
  Mean Change* at Week 6** -28.1 -3.7 -24.4 —
-15
* LS mean change, treatment difference and p-value are based on an analysis using an
ANCOVA model with baseline weekly endpoint as covariate and treatment group, etiology -20 *
at study entry (spinal cord injury or multiple sclerosis), concurrent anticholinergic therapy
at screening, and investigator as factors. LOCF values were used to analyze the primary
efficacy variable. -25
** Primary timepoint 0 2 6 12
a
Primary endpoint Weeks Post-Treatment
b
Secondary endpoint
Table 19: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode
Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during The median duration of response in study NDO-1 and NDO-2, based on patient qualification
First Involuntary Detrusor Contraction (cmH2O) in Study NDO-2 for re-treatment was 295-337 days (42-48 weeks) for the 200 Units dose group compared
BOTOX Placebo Treatment to 96-127 days (13-18 weeks) for placebo. Re-treatment was based on loss of effect on
p-value* incontinence episode frequency (50% of effect in Study NDO-1; 70% of effect in Study
200 Units Difference*
NDO-2).
Weekly Frequency of Urinary
Incontinence Episodesa 14.3 Chronic Migraine
BOTOX was evaluated in two randomized, multi-center, 24-week, 2 injection cycle, placebo-
 N 91 91 controlled double-blind studies. Study 1 and Study 2 included chronic migraine adults
  Mean Baseline 32.7 36.8 who were not using any concurrent headache prophylaxis, and during a 28-day baseline
period had ≥15 headache days lasting 4 hours or more, with ≥50% being migraine/
  Mean Change* at Week 2 -18.0 -7.9 -10.1 — probable migraine. In both studies, patients were randomized to receive placebo or 155
Units to 195 Units BOTOX injections every 12 weeks for the 2-cycle, double-blind phase.
-8.8
  Mean Change* at Week 6** -19.6 -10.8 p=0.003 Patients were allowed to use acute headache treatments during the study. BOTOX treatment
(-14.5, -3.0)
demonstrated statistically significant and clinically meaningful improvements from baseline
  Mean Change* at Week 12 -19.6 -10.7 -8.9 — compared to placebo for key efficacy variables (see Table 20).
Maximum Cystometric Table 20: Week 24 Key Efficacy Variables for Study 1 and Study 2
Capacityb (mL) Study 1 Study 2
 N 88 85 Efficacy per 28 days BOTOX Placebo BOTOX Placebo
  Mean Baseline 239.6 253.8 (N=341) (N=338) (N=347) (N=358)
  Mean Change* at Week 6** 150.8 2.8 148.0 p<0.001 Change from baseline in frequency
-7.8* -6.4 -9.2* -6.9
(101.8, 194.2) of headache days
Maximum Detrusor Pressure Change from baseline in total
during First Involuntary cumulative hours of headache on -107* -70 -134* -95
Detrusor Contractionb (cmH2O) headache days
 N 29 68 * Significantly different from placebo (p≤0.05)
  Mean Baseline 65.6 43.7 Patients treated with BOTOX had a significantly greater mean decrease from baseline in
the frequency of headache days at most timepoints from Week 4 to Week 24 in Study 1
  Mean Change* at Week 6** -28.7 2.1 -30.7 — (Figure 8), and all timepoints from Week 4 to Week 24 in Study 2 (Figure 9), compared to
* LS mean change, treatment difference and p-value are based on an analysis using an placebo-treated patients.
ANCOVA model with baseline weekly endpoint as covariate and treatment group, etiology
at study entry (spinal cord injury or multiple sclerosis), concurrent anticholinergic therapy
at screening, and investigator as factors. LOCF values were used to analyze the primary
efficacy variable.
** Primary timepoint
a
Primary endpoint
b
Secondary endpoint
Figure 8: Mean Change from Baseline in Number of Headache Days for Study 1 Key secondary endpoints included Physician Global Assessment, finger flexors muscle
0
tone, and thumb flexors tone at Week 6. The Physician Global Assessment evaluated the
Treatment
response to treatment in terms of how the patient was doing in his/her life using a scale
Placebo
Mean Change From Baseline (± Std Err) (n = 338) from -4 = very marked worsening to +4 = very marked improvement. Study 1 results
-2 on the primary endpoint and the key secondary endpoints are shown in Table 22.
BOTOX®
(n = 341) Table 22: Primary and Key Secondary Endpoints by Muscle Group at Week 6 in Study 1
Headache Days:

-4 *: p ≤ 0.05 BOTOX Placebo

(N=64) (N=62)
-6 * Median Change from Baseline in Wrist Flexor Muscle Tone
on the Ashworth Scale†a -2.0* 0.0
* Median Change from Baseline in Finger Flexor Muscle
-8 * Tone on the Ashworth Scale††b -1.0* 0.0
* *
Median Change from Baseline in Thumb Flexor Muscle
-10 Tone on the Ashworth Scale††c -1.0 -1.0
Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Median Physician Global Assessment of Response
Visit to Treatment†† 2.0* 0.0
†
Primary endpoint at Week 6
Figure 9: Mean Change from Baseline in Number of Headache Days for Study 2 ††
Secondary endpoints at Week 6
0 * Significantly different from placebo (p≤0.05)
Treatment a
BOTOX injected into both the flexor carpi radialis and ulnaris muscles
Placebo
Mean Change From Baseline (± Std Err)

(n = 358)
b
BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles
-2
c
BOTOX injected into the adductor pollicis and flexor pollicis longus muscles
BOTOX®
(n = 347) Study 2 compared 3 doses of BOTOX with placebo and included 91 patients [BOTOX 360
Units (N=21), BOTOX 180 Units (N=23), BOTOX 90 Units (N=21), and placebo (N=26)] with
Headache Days:

-4 *: p ≤ 0.05 upper limb spasticity (expanded Ashworth score of at least 2 for elbow flexor tone and at
least 3 for wrist flexor tone) who were at least 6 weeks post-stroke. BOTOX and placebo
-6 were injected with EMG guidance into the flexor digitorum profundus, flexor digitorum
* sublimis, flexor carpi radialis, flexor carpi ulnaris, and biceps brachii (see Table 23).
Table 23: Study Medication Dose and Injection Sites in Study 2 and Study 3
-8
* * Total Dose
* BOTOX BOTOX BOTOX Volume Injection
-10 * *
Muscles Injected low dose mid dose high dose (mL) Sites
Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
(90 Units) (180 Units) (360 Units) per site (n)
Visit Wrist
Flexor Carpi Ulnaris 10 Units 20 Units 40 Units 0.4 1
14.4 Upper Limb Spasticity Flexor Carpi Radialis 15 Units 30 Units 60 Units 0.6 1
The efficacy of BOTOX for the treatment of upper limb spasticity was evaluated in three
randomized, multi-center, double-blind, placebo-controlled studies (Studies 1, 2, and 3). Two Finger
7.5 Units 15 Units 30 Units 0.3 1
additional randomized, multi-center, double-blind, placebo-controlled studies for upper limb Flexor Digitorum Profundus
spasticity in adults also included the evaluation of the efficacy of BOTOX for the treatment of Flexor Digitorum Sublimis 7.5 Units 15 Units 30 Units 0.3 1
thumb spasticity (Studies 4 and 5).
Elbow
Study 1 included 126 patients (64 BOTOX and 62 placebo) with upper limb spasticity 50 Units 100 Units 200 Units 0.5 4
Biceps Brachii
(Ashworth score of at least 3 for wrist flexor tone and at least 2 for finger flexor tone) who
were at least 6 months post-stroke. BOTOX (a total dose of 200 Units to 240 Units) and The primary efficacy variable in Study 2 was the wrist flexor tone at Week 6 as measured by
placebo were injected intramuscularly (IM) into the flexor digitorum profundus, flexor digitorum the expanded Ashworth Scale. The expanded Ashworth Scale uses the same scoring system
sublimis, flexor carpi radialis, flexor carpi ulnaris, and if necessary into the adductor pollicis as the Ashworth Scale, but allows for half-point increments.
and flexor pollicis longus (see Table 21). Use of an EMG/nerve stimulator was recommended to Key secondary endpoints in Study 2 included Physician Global Assessment, finger flexors
assist in proper muscle localization for injection. Patients were followed for 12 weeks. muscle tone, and elbow flexors muscle tone at Week 6. Study 2 results on the primary
Table 21: Study Medication Dose and Injection Sites in Study 1 endpoint and the key secondary endpoints at Week 6 are shown in Table 24.
BOTOX Number of Table 24: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at
Muscles Injected Volume (mL) Week 6 in Study 2
(Units) Injection Sites
Wrist BOTOX BOTOX BOTOX
Flexor Carpi Radialis 1 50 1 low dose mid dose high dose Placebo
(90 Units) (180 Units) (360 Units) (N=26)
Flexor Carpi Ulnaris 1 50 1 (N=21) (N=23) (N=21)
Finger Median Change from Baseline in
Flexor Digitorum Profundus 1 50 1 Wrist Flexor Muscle Tone on the -1.5* -1.0* -1.5* -1.0
Flexor Digitorum Sublimis 1 50 1 Ashworth Scale†b
Median Change from Baseline in
Thumb
Finger Flexor Muscle Tone on the -0.5 -0.5 -1.0 -0.5
Adductor Pollicisa 0.4 20 1
Ashworth Scale††c
Flexor Pollicis Longus a
0.4 20 1 Median Change from Baseline in
a
injected only if spasticity is present in this muscle Elbow Flexor Muscle Tone on the -0.5 -1.0* -0.5a -0.5
Ashworth Scale††d
The primary efficacy variable was wrist flexors muscle tone at week 6, as measured by the
Ashworth score. The Ashworth Scale is a clinical measure of the force required to move an Median Physician Global
extremity around a joint, with a reduction in score clinically representing a reduction in the Assessment of Response 1.0* 1.0* 1.0* 0.0
force needed to move a joint (i.e., improvement in spasticity). to Treatment
Possible scores range from 0 to 4: †
Primary endpoint at Week 6
0 = No increase in muscle tone (none) ††
Secondary endpoints at Week 6
1 = Slight increase in muscle tone, giving a ‘catch’ when the limb was moved in flexion or * Significantly different from placebo (p≤0.05)
extension (mild) a
p=0.053
2 = More marked increase in muscle tone but affected limb is easily flexed (moderate) b
Total dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles
3 = Considerable increase in muscle tone - passive movement difficult (severe) c
Total dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum
4 = Limb rigid in flexion or extension (very severe). sublimis muscles
d
Dose of BOTOX injected into biceps brachii muscle
Study 3 compared 3 doses of BOTOX with placebo and enrolled 88 patients [BOTOX Table 28: Efficacy Endpoints for Thumb Flexors at Week 6 in Study 5
360 Units (N=23), BOTOX 180 Units (N=23), BOTOX 90 Units (N=23), and placebo (N=19)]
with upper limb spasticity (expanded Ashworth score of at least 2 for elbow flexor tone BOTOX BOTOX
Placebo Placebo
and at least 3 for wrist flexor tone and/or finger flexor tone) who were at least 6 weeks low dose high dose
low dose high dose
post-stroke. BOTOX and placebo were injected with EMG guidance into the flexor digitorum (30 Units) (40 Units)
(N=9) (N=23)
profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and biceps (N=14) (N=43)
brachii (see Table 23). Median Change from Baseline
The primary efficacy variable in Study 3 was wrist and elbow flexor tone as measured by in Thumb Flexor Muscle Tone on -1.0 -1.0 -0.5* 0.0
the expanded Ashworth score. A key secondary endpoint was assessment of finger flexors the modified Ashworth Scale†††a
muscle tone. Study 3 results on the primary endpoint at Week 4 are shown in Table 25. Median change from Baseline in
Table 25: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at Clinical Global Impression Score 1.0 0.0 2.0* 0.0
Week 4 in Study 3 by Physician††
BOTOX BOTOX BOTOX ††
Secondary endpoint at Week 6
low dose mid dose high dose Placebo †††
Other endpoint at Week 6
(90 Units) (180 Units) (360 Units) (N=19) * Significantly different from placebo (p≤0.010)
(N=23) (N=21) (N=22) a
BOTOX injected into the adductor pollicis and flexor pollicis longus muscles
Median Change from Baseline in 14.5 Cervical Dystonia
Wrist Flexor Muscle Tone on the -1.0 -1.0 -1.5* -0.5 A randomized, multi-center, double-blind, placebo-controlled study of the treatment of
Ashworth Scale†b cervical dystonia was conducted. This study enrolled adult patients with cervical dystonia
and a history of having received BOTOX in an open label manner with perceived good
Median Change from Baseline in
response and tolerable side effects. Patients were excluded if they had previously received
Finger Flexor Muscle Tone on the -1.0 -1.0 -1.0* -0.5
surgical or other denervation treatment for their symptoms or had a known history of
Ashworth Scale††c
neuromuscular disorder. Subjects participated in an open label enrichment period where
Median Change from Baseline in they received their previously employed dose of BOTOX. Only patients who were again
Elbow Flexor Muscle Tone on the -0.5 -0.5 -1.0* -0.5 perceived as showing a response were advanced to the randomized evaluation period.
Ashworth Scale†d The muscles in which the blinded study agent injections were to be administered were
determined on an individual patient basis.
†
Primary endpoint at Week 4
There were 214 subjects evaluated for the open label period, of which 170 progressed
††
Secondary endpoints at Week 4
into the randomized, blinded treatment period (88 in the BOTOX group, 82 in the placebo
* Significantly different from placebo (p≤0.05)
group). Patient evaluations continued for at least 10 weeks post-injection. The primary
b
Total dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles
outcome for the study was a dual endpoint, requiring evidence of both a change in the
c
Total dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum
Cervical Dystonia Severity Scale (CDSS) and an increase in the percentage of patients
sublimis muscles
showing any improvement on the Physician Global Assessment Scale at 6 weeks after the
d
Dose of BOTOX injected into biceps brachii muscle
injection session. The CDSS quantifies the severity of abnormal head positioning and was
Study 4 included 170 patients (87 BOTOX and 83 placebo) with upper limb spasticity who newly devised for this study. CDSS allots 1 point for each 5 degrees (or part thereof) of head
were at least 6 months post-stroke. In Study 4, patients received 20 Units of BOTOX into the deviation in each of the three planes of head movement (range of scores up to theoretical
adductor pollicis and flexor pollicis longus (total BOTOX dose =40 Units in thumb muscles) maximum of 54). The Physician Global Assessment Scale is a 9 category scale scoring the
or placebo (see Table 26). Study 5 included 109 patients with upper limb spasticity who physician’s evaluation of the patients’ status compared to baseline, ranging from –4 to
were at least 6 months post-stroke. In Study 5, patients received 15 Units (low dose) or +4 (very marked worsening to complete improvement), with 0 indicating no change from
20 Units (high dose) of BOTOX into the adductor pollicis and flexor pollicis longus under baseline and +1 slight improvement. Pain is also an important symptom of cervical dystonia
EMG guidance (total BOTOX low dose =30 Units, total BOTOX high dose =40 Units), or and was evaluated by separate assessments of pain frequency and severity on scales of
placebo (see Table 26). The duration of follow-up in Study 4 and Study 5 was 12 weeks. 0 (no pain) to 4 (constant in frequency or extremely severe in intensity). Study results on
Table 26: Study Medication Dose and Injection Sites in Studies 4 and 5 the primary endpoints and the pain-related secondary endpoints are shown in Table 29.
Study 4 Study 5 Table 29: Efficacy Outcomes of the Phase 3 Cervical Dystonia Study (Group Means)
Number
BOTOX BOTOX Volume Volume of Injection Placebo BOTOX 95% CI on
Muscles (N=82) (N=88) Difference
BOTOX Volume low high low high Sites for
Injected
(Units) (mL) dose dose dose dose Studies Baseline CDSS 9.3 9.2
(Units) (Units) (mL) (mL) 4 and 5
Change in CDSS at Week 6 -0.3 -1.3 (-2.3, 0.3)[a,b]
Thumb
Adductor 20 0.4 15 20 0.3 0.4 1 % Patients with Any Improvement on
31% 51% (5%, 34%)[a]
Pollicis Physician Global Assessment

Flexor Pain Intensity Baseline 1.8 1.8

Pollicis 20 0.4 15 20 0.3 0.4 1 Change in Pain Intensity at Week 6 -0.1 -0.4 (-0.7, -0.2)[c]
Longus
Pain Frequency Baseline 1.9 1.8
The results of Study 4 for the change from Baseline to Week 6 in thumb flexor tone Change in Pain Frequency at Week 6 -0.0 -0.3 (-0.5, -0.0)[c]
measured by modified Ashworth Scale and overall treatment response by Physician Global
Assessment at week 6 are presented in Table 27. [a]
Confidence intervals are constructed from the analysis of covariance table with treatment
Table 27: Efficacy Endpoints for Thumb Flexors at Week 6 in Study 4 and investigational site as main effects, and baseline CDSS as a covariate.
[b]
These values represent the prospectively planned method for missing data imputation
BOTOX Placebo and statistical test. Sensitivity analyses indicated that the 95% confidence interval
(N=66) (N=57) excluded the value of no difference between groups and the p-value was less than 0.05.
Median Change from Baseline in Thumb Flexor These analyses included several alternative missing data imputation methods and non-
-1.0* 0.0 parametric statistical tests.
Muscle Tone on the modified Ashworth Scale††a [c]
Confidence intervals are based on the t-distribution.
Median Physician Global Assessment of
2.0* 0.0 Exploratory analyses of this study suggested that the majority of patients who had shown
Response to Treatment††
a beneficial response by week 6 had returned to their baseline status by 3 months after
††
Secondary endpoints at Week 6 treatment. Exploratory analyses of subsets by patient sex and age suggest that both sexes
* Significantly different from placebo (p≤0.001) receive benefit, although female patients may receive somewhat greater amounts than
a
BOTOX injected into the adductor pollicis and flexor pollicis longus muscles male patients. There is a consistent treatment-associated effect between subsets greater
than and less than age 65. There were too few non-Caucasian patients enrolled to draw any
In Study 5, the results of the change from Baseline to Week 6 in thumb flexor tone conclusions regarding relative efficacy in racial subsets.
measured by modified Ashworth Scale and Clinical Global Impression (CGI) of functional
assessment scale assessed by the physician using an 11-point Numeric Rating Scale In this study the median total BOTOX dose in patients randomized to receive BOTOX (N=88)
[-5 worst possible function to +5 best possible function]) are presented in Table 28. was 236 Units, with 25th to 75th percentile ranges of 198 Units to 300 Units. Of these 88
patients, most received injections to 3 or 4 muscles; 38 received injections to 3 muscles,
28 to 4 muscles, 5 to 5 muscles, and 5 to 2 muscles. The dose was divided amongst the
affected muscles in quantities shown in Table 30. The total dose and muscles selected were
tailored to meet individual patient needs.
Table 30: Number of Patients Treated per Muscle and Fraction of Total Dose Injected 14.7 Blepharospasm
into Involved Muscles Botulinum toxin has been investigated for use in patients with blepharospasm in
several studies. In an open label, historically controlled study, 27 patients with essential
Number of blepharospasm were injected with 2 Units of BOTOX at each of six sites on each side.
Mid-Range of
Patients Treated Mean % Dose Twenty-five of the 27 patients treated with botulinum toxin reported improvement within
Muscle % Dose per
in this Muscle per Muscle 48 hours. One patient was controlled with a higher dosage at 13 weeks post initial injection
Muscle*
(N=88) and one patient reported mild improvement but remained functionally impaired.
Splenius capitis/cervicis 83 38 25-50 In another study, 12 patients with blepharospasm were evaluated in a double-blind,
Sternocleidomastoid 77 25 17-31 placebo-controlled study. Patients receiving botulinum toxin (n=8) improved compared
with the placebo group (n=4). The effects of the treatment lasted a mean of 12 weeks.
Levator scapulae 52 20 16-25
One thousand six hundred eighty-four patients with blepharospasm who were evaluated in
Trapezius 49 29 18-33 an open label trial showed clinical improvement as evaluated by measured eyelid force and
clinically observed intensity of lid spasm, lasting an average of 12 weeks prior to the need
Semispinalis 16 21 13-25 for re-treatment.
Scalene 15 15 6-21 14.8 Strabismus
Longissimus 8 29 17-41 Six hundred seventy-seven patients with strabismus treated with one or more injections
of BOTOX were evaluated in an open label trial. Fifty-five percent of these patients
* The mid-range of dose is calculated as the 25th to 75th percentiles. improved to an alignment of 10 prism diopters or less when evaluated six months
There were several randomized studies conducted prior to the double-blind, placebo- or more following injection.
controlled study, which were supportive but not adequately designed to assess or 16 HOW SUPPLIED/STORAGE AND HANDLING
quantitatively estimate the efficacy of BOTOX. BOTOX is supplied in a single-use vial in the following sizes:
14.6 Primary Axillary Hyperhidrosis 100 Units NDC 0023-1145-01
The efficacy and safety of BOTOX for the treatment of primary axillary hyperhidrosis 200 Units NDC 0023-3921-02
were evaluated in two randomized, multi-center, double-blind, placebo-controlled studies. Vials of BOTOX have a holographic film on the vial label that contains the name “Allergan”
Study 1 included adult patients with persistent primary axillary hyperhidrosis who scored within horizontal lines of rainbow color. In order to see the hologram, rotate the vial back
3 or 4 on a Hyperhidrosis Disease Severity Scale (HDSS) and who produced at least and forth between your fingers under a desk lamp or fluorescent light source. (Note: the
50 mg of sweat in each axilla at rest over 5 minutes. HDSS is a 4-point scale with holographic film on the label is absent in the date/lot area.) If you do not see the lines of
1 = “underarm sweating is never noticeable and never interferes with my daily activities”; rainbow color or the name “Allergan”, do not use the product and contact Allergan for
to 4 = “underarm sweating is intolerable and always interferes with my daily activities”. additional information at 1-800-890-4345 from 7:00 AM to 3:00 PM Pacific Time.
A total of 322 patients were randomized in a 1:1:1 ratio to treatment in both axillae with Storage
either 50 Units of BOTOX, 75 Units of BOTOX, or placebo. Patients were evaluated at 4-week Unopened vials of BOTOX should be stored in a refrigerator (2° to 8°C) for up to 36 months.
intervals. Patients who responded to the first injection were re-injected when they reported Do not use after the expiration date on the vial. Administer BOTOX within 24 hours of
a re-increase in HDSS score to 3 or 4 and produced at least 50 mg sweat in each axilla by reconstitution; during this period reconstituted BOTOX should be stored in a refrigerator
gravimetric measurement, but no sooner than 8 weeks after the initial injection. (2° to 8°C). Reconstituted BOTOX should be clear, colorless, and free of particulate matter.
Study responders were defined as patients who showed at least a 2-grade improvement
17 PATIENT COUNSELING INFORMATION
from baseline value on the HDSS 4 weeks after both of the first two treatment sessions or
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
had a sustained response after their first treatment session and did not receive re-treatment
during the study. Spontaneous resting axillary sweat production was assessed by weighing Swallowing, Speaking or Breathing Difficulties, or Other Unusual Symptoms
a filter paper held in the axilla over a period of 5 minutes (gravimetric measurement). Advise patients to inform their doctor or pharmacist if they develop any unusual symptoms
Sweat production responders were those patients who demonstrated a reduction in axillary (including difficulty with swallowing, speaking, or breathing), or if any existing symptom
sweating from baseline of at least 50% at week 4. worsens [see Boxed Warning and Warnings and Precautions (5.2, 5.6)].
In the three study groups the percentage of patients with baseline HDSS score of 3 ranged Ability to Operate Machinery or Vehicles
from 50% to 54% and from 46% to 50% for a score of 4. The median amount of sweat Advise patients that if loss of strength, muscle weakness, blurred vision, or drooping eyelids
production (averaged for each axilla) was 102 mg, 123 mg, and 114 mg for the placebo, occur, they should avoid driving a car or engaging in other potentially hazardous activities.
50 Units and 75 Units groups respectively. Voiding Symptoms after Bladder Injections
The percentage of responders based on at least a 2-grade decrease from baseline in HDSS After bladder injections for urinary incontinence, advise patients to contact their physician if
or based on a >50% decrease from baseline in axillary sweat production was greater in they experience difficulties in voiding or burning sensation upon voiding.
both BOTOX groups than in the placebo group (p<0.001), but was not significantly different
between the two BOTOX doses (see Table 31).
MEDICATION GUIDE
Duration of response was calculated as the number of days between injection and the date
of the first visit at which patients returned to 3 or 4 on the HDSS scale. The median duration BOTOX®
of response following the first treatment in BOTOX treated patients with either dose was BOTOX® Cosmetic
201 days. Among those who received a second BOTOX injection, the median duration of (Boe-tox)
response was similar to that observed after the first treatment. (onabotulinumtoxinA)
In study 2, 320 adults with bilateral axillary primary hyperhidrosis were randomized for Injection
to receive either 50 Units of BOTOX (n=242) or placebo (n=78). Treatment responders
were defined as subjects showing at least a 50% reduction from baseline in axillary Read the Medication Guide that comes with BOTOX or BOTOX Cosmetic
sweating measured by gravimetric measurement at 4 weeks. At week 4 post-injection, the before you start using it and each time it is given to you. There may be
percentages of responders were 91% (219/242) in the BOTOX group and 36% (28/78) in new information. This information does not take the place of talking with
the placebo group, p<0.001. The difference in percentage of responders between BOTOX your doctor about your medical condition or your treatment. You should
and placebo was 55% (95% CI=43.3, 65.9).
share this information with your family members and caregivers.
Table 31: Study 1 - Study Outcomes
What is the most important information I should know about BOTOX
BOTOX BOTOX BOTOX BOTOX
Treatment
50 Units 75 Units
Placebo
50-placebo 75-placebo
and BOTOX Cosmetic?
Response (N=108)
(N=104) (N=110) (95% CI) (95% CI) BOTOX and BOTOX Cosmetic may cause serious side effects that can
HDSS Score 55% (57) 49% (54) 6% (6) 49.3% 43% be life threatening, including:
change ≥2 (n)a (38.8, 59.7) (33.2, 53.8) • Problems breathing or swallowing
>50% decrease
81% (84) 86% (94) 41% (44) 40% 45%
• Spread of toxin effects
in axillary sweat These problems can happen hours, days, to weeks after an injection
(28.1, 52.0) (33.3, 56.1)
production % (n)
of BOTOX or BOTOX Cosmetic. Call your doctor or get medical help
Patients who showed at least a 2-grade improvement from baseline value on the HDSS
a right away if you have any of these problems after treatment with
4 weeks after both of the first two treatment sessions or had a sustained response after BOTOX or BOTOX Cosmetic:
their first treatment session and did not receive re-treatment during the study.
1. Problems swallowing, speaking, or breathing. These problems BOTOX Cosmetic is a prescription medicine that is injected into the area
can happen hours, days, to weeks after an injection of BOTOX or around the side of the eyes to improve the look of crow’s feet lines in
BOTOX Cosmetic usually because the muscles that you use to breathe adults for a short period of time (temporary).
and swallow can become weak after the injection. Death can happen You may receive treatment for frown lines and crow’s feet lines at the
as a complication if you have severe problems with swallowing or same time.
breathing after treatment with BOTOX or BOTOX Cosmetic.
• People with certain breathing problems may need to use muscles in It is not known whether BOTOX is safe or effective in people
their neck to help them breathe. These people may be at greater risk younger than:
for serious breathing problems with BOTOX or BOTOX Cosmetic. • 18 years of age for treatment of urinary incontinence
• Swallowing problems may last for several months. People who • 18 years of age for treatment of chronic migraine
cannot swallow well may need a feeding tube to receive food and • 18 years of age for treatment of spasticity
water. If swallowing problems are severe, food or liquids may go • 16 years of age for treatment of cervical dystonia
into your lungs. People who already have swallowing or breathing • 18 years of age for treatment of hyperhidrosis
problems before receiving BOTOX or BOTOX Cosmetic have the • 12 years of age for treatment of strabismus or blepharospasm
highest risk of getting these problems.
BOTOX Cosmetic is not recommended for use in children younger than
2. Spread of toxin effects. In some cases, the effect of botulinum toxin 18 years of age.
may affect areas of the body away from the injection site and cause
symptoms of a serious condition called botulism. The symptoms of It is not known whether BOTOX and BOTOX Cosmetic are safe or
botulism include: effective to prevent headaches in people with migraine who have 14
• loss of strength and muscle weakness all over the body or fewer headache days each month (episodic migraine).
• double vision It is not known whether BOTOX and BOTOX Cosmetic are safe or
• blurred vision and drooping eyelids effective for other types of muscle spasms or for severe sweating
• hoarseness or change or loss of voice (dysphonia) anywhere other than your armpits.
• trouble saying words clearly (dysarthria) Who should not take BOTOX or BOTOX Cosmetic?
• loss of bladder control Do not take BOTOX or BOTOX Cosmetic if you:
• trouble breathing • are allergic to any of the ingredients in BOTOX or BOTOX Cosmetic.
• trouble swallowing See the end of this Medication Guide for a list of ingredients in
These symptoms can happen hours, days, to weeks after you receive an BOTOX and BOTOX Cosmetic.
injection of BOTOX or BOTOX Cosmetic. • had an allergic reaction to any other botulinum toxin product such as
Myobloc ®, Dysport ®, or Xeomin ®
These problems could make it unsafe for you to drive a car or do other
dangerous activities. See “What should I avoid while receiving BOTOX or • have a skin infection at the planned injection site
BOTOX Cosmetic?” • are being treated for urinary incontinence and have a urinary tract
infection (UTI)
There has not been a confirmed serious case of spread of toxin effect • are being treated for urinary incontinence and find that you cannot
away from the injection site when BOTOX has been used at the empty your bladder on your own (only applies to people who are not
recommended dose to treat chronic migraine, severe underarm sweating, routinely catheterizing)
blepharospasm, or strabismus, or when BOTOX Cosmetic has been used
at the recommended dose to treat frown lines and/or crow’s feet lines. What should I tell my doctor before taking BOTOX or
BOTOX Cosmetic?
What are BOTOX and BOTOX Cosmetic?
Tell your doctor about all your medical conditions, including if you:
BOTOX is a prescription medicine that is injected into muscles and used: • have a disease that affects your muscles and nerves (such as
• to treat overactive bladder symptoms such as a strong need to amyotrophic lateral sclerosis [ALS or Lou Gehrig’s disease],
urinate with leaking or wetting accidents (urge urinary incontinence), myasthenia gravis or Lambert-Eaton syndrome). See “What is the
a strong need to urinate right away (urgency), and urinating often most important information I should know about BOTOX and
(frequency) in adults when another type of medicine (anticholinergic) BOTOX Cosmetic?”
does not work well enough or cannot be taken. • have allergies to any botulinum toxin product
• to treat leakage of urine (incontinence) in adults with overactive • had any side effect from any botulinum toxin product in the past
bladder due to neurologic disease when another type of medicine
(anticholinergic) does not work well enough or cannot be taken. • have or have had a breathing problem, such as asthma
or emphysema
• to prevent headaches in adults with chronic migraine who have
15 or more days each month with headache lasting 4 or more hours • have or have had swallowing problems
each day. • have or have had bleeding problems
• to treat increased muscle stiffness in elbow, wrist, and finger • have plans to have surgery
muscles in adults with upper limb spasticity. • had surgery on your face
• to treat the abnormal head position and neck pain that happens with • have weakness of your forehead muscles, such as trouble raising
cervical dystonia (CD) in adults. your eyebrows
• to treat certain types of eye muscle problems (strabismus) or • have drooping eyelids
abnormal spasm of the eyelids (blepharospasm) in people 12 years • have any other change in the way your face normally looks
and older. • have symptoms of a urinary tract infection (UTI) and are being
BOTOX is also injected into the skin to treat the symptoms of severe treated for urinary incontinence. Symptoms of a urinary tract
underarm sweating (severe primary axillary hyperhidrosis) when infection may include pain or burning with urination, frequent
medicines used on the skin (topical) do not work well enough. urination, or fever.
• have problems emptying your bladder on your own and are being
BOTOX Cosmetic is a prescription medicine that is injected into treated for urinary incontinence
muscles and used to improve the look of moderate to severe frown • are pregnant or plan to become pregnant. It is not known if BOTOX
lines between the eyebrows (glabellar lines) in adults for a short period or BOTOX Cosmetic can harm your unborn baby.
of time (temporary). • are breast-feeding or plan to breastfeed. It is not known if BOTOX or
BOTOX Cosmetic passes into breast milk.
Tell your doctor about all the medicines you take, including Other side effects of BOTOX and BOTOX Cosmetic include:
prescription and nonprescription medicines, vitamins and herbal • dry mouth
products. Using BOTOX or BOTOX Cosmetic with certain other • discomfort or pain at the injection site
medicines may cause serious side effects. Do not start any new • tiredness
medicines until you have told your doctor that you have received • headache
BOTOX or BOTOX Cosmetic in the past.
• neck pain
Especially tell your doctor if you: • eye problems: double vision, blurred vision, decreased eyesight,
• have received any other botulinum toxin product in the last drooping eyelids, swelling of your eyelids, and dry eyes.
four months • urinary tract infection in people being treated for urinary
• have received injections of botulinum toxin, such as Myobloc ® incontinence
(rimabotulinumtoxinB), Dysport ® (abobotulinumtoxinA), or Xeomin ® • painful urination in people being treated for urinary incontinence
(incobotulinumtoxinA) in the past. Be sure your doctor knows exactly • inability to empty your bladder on your own and are being treated
which product you received. for urinary incontinence. If you have difficulty fully emptying your
• have recently received an antibiotic by injection bladder after getting BOTOX, you may need to use disposable
• take muscle relaxants self-catheters to empty your bladder up to a few times each day
• take an allergy or cold medicine until your bladder is able to start emptying again.
• take a sleep medicine • allergic reactions. Symptoms of an allergic reaction to BOTOX
• take anti-platelets (aspirin-like products) and/or anti-coagulants or BOTOX Cosmetic may include: itching, rash, red itchy welts,
(blood thinners) wheezing, asthma symptoms, or dizziness or feeling faint. Tell your
doctor or get medical help right away if you are wheezing or have
Ask your doctor if you are not sure if your medicine is one that is asthma symptoms, or if you become dizzy or faint.
listed above.
Tell your doctor if you have any side effect that bothers you or that does
Know the medicines you take. Keep a list of your medicines with you to not go away.
show your doctor and pharmacist each time you get a new medicine.
These are not all the possible side effects of BOTOX and
How should I take BOTOX or BOTOX Cosmetic? BOTOX Cosmetic. For more information, ask your doctor or pharmacist.
• BOTOX or BOTOX Cosmetic is an injection that your doctor will
give you. Call your doctor for medical advice about side effects. You may report
• BOTOX is injected into your affected muscles, skin, or bladder. side effects to FDA at 1-800-FDA-1088.
• BOTOX Cosmetic is injected into your affected muscles. General information about BOTOX and BOTOX Cosmetic:
• Your doctor may change your dose of BOTOX or BOTOX Cosmetic, Medicines are sometimes prescribed for purposes other than those listed
until you and your doctor find the best dose for you. in a Medication Guide.
• Your doctor will tell you how often you will receive your dose This Medication Guide summarizes the most important information
of BOTOX or BOTOX Cosmetic injections. about BOTOX and BOTOX Cosmetic. If you would like more information,
What should I avoid while taking BOTOX or BOTOX Cosmetic? talk with your doctor. You can ask your doctor or pharmacist for
information about BOTOX and BOTOX Cosmetic that is written for
BOTOX and BOTOX Cosmetic may cause loss of strength or general
healthcare professionals.
muscle weakness, or vision problems within hours to weeks of taking
BOTOX or BOTOX Cosmetic. If this happens, do not drive a car, What are the ingredients in BOTOX and BOTOX Cosmetic?
operate machinery, or do other dangerous activities. See “What is Active ingredient: botulinum toxin type A
the most important information I should know about BOTOX and Inactive ingredients: human albumin and sodium chloride
BOTOX Cosmetic?” Revised: 08/2015
What are the possible side effects of BOTOX and BOTOX Cosmetic? This Medication Guide has been approved by the U.S. Food and Drug
BOTOX and BOTOX Cosmetic can cause serious side effects. See Administration.
“What is the most important information I should know about BOTOX Manufactured by: Allergan Pharmaceuticals Ireland
and BOTOX Cosmetic?” a subsidiary of: Allergan, Inc.
2525 Dupont Dr.
Irvine, CA 92612
© 2015 Allergan. All rights reserved.
®
marks owned by Allergan, Inc.
Patented. See: www.allergan.com/products/patent_notices
Myobloc ® is a registered trademark of Solstice Neurosciences, Inc.
Dysport ® is a registered trademark of Ipsen Biopharm Limited Company.
Xeomin ® is a registered trademark of Merz Pharma GmbH & Co KGaA.

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