HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BOTOX® Cosmetic safely and effectively. See full prescribing information for BOTOX Cosmetic.

BOTOX Cosmetic (onabotulinumtoxinA) for injection, for intramuscular use

Initial U.S. Approval: 1989

RECENT MAJOR CHANGES

Warnings and Precautions, Dry Eye in Patients Treated with BOTOX Cosmetic (5.10) 11/2019

INDICATIONS AND USAGE BOTOX Cosmetic is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated in adult patients for the temporary improvement in the appearance of (1):

Moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity

Moderate to severe lateral canthal lines associated with orbicularis oculi activity

Moderate to severe forehead lines associated with frontalis muscle activity DOSAGE AND ADMINISTRATION

Botox Cosmetic is administered by intramuscular injection

Glabellar Lines Administration: 0.1 mL (4 Units) into each of 5 sites, for a total dose of 20 Units (2.3)

Lateral Canthal Lines Administration: 0.1 mL (4 Units) into each of 3 sites per side (6 total injection points), for a total of 24 Units (2.3)

Forehead Lines Administration: 0.1 mL (4 Units) into each of 5 forehead line sites (20 Units) with 0.1 mL (4 Units) into each of 5 glabellar line sites

(20 Units), for a recommended total of 40 Units (2.3)

Follow dosage and administration recommendations. In treating adults for more than one approved indications with BOTOX and BOTOX Cosmetic, do not exceed a total dose of 400 Units administered in a 3 month interval

(2.1)

See Preparation and Dilution Technique for instructions on BOTOX Cosmetic reconstitution, storage, and preparation before injection (2.2) DOSAGE FORMS AND STRENGTHS For Injection: 50 Units or 100 Units vacuum-dried powder in a single-dose vial for reconstitution (3)

CONTRAINDICATIONS

Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation (4.1, 5.4)

Infection at the injection site (4.2)

WARNINGS AND PRECAUTIONS

Potency Units of BOTOX Cosmetic are not interchangeable with other preparations of botulinum toxin products (5.1, 11)

Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek immediate medical attention if respiratory, speech or swallowing difficulties occur (5.2, 5.7)

Potential serious adverse reactions after administration of BOTOX for unapproved uses (5.3)

Adverse event reports have been received involving the cardiovascular system, some with fatal outcomes. Use caution when administering to patients with pre-existing cardiovascular disease. (5.5)

Concomitant neuromuscular disorder may exacerbate clinical effects of treatment (5.6)

Use with caution in patients with compromised respiratory function or dysphagia (5.7)

ADVERSE REACTIONS The most common adverse reactions are (6.1):

Glabellar Lines: eyelid ptosis (3%)

Lateral Canthal Lines: eyelid edema (1%)

Forehead Lines: headache (9%) and brow ptosis (2%) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-***-**** or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Patients receiving concomitant treatment of BOTOX Cosmetic and aminoglycosides or other agents interfering with neuromuscular transmission

(e.g., curare-like agents), or muscle relaxants, should be observed closely because the effect of BOTOX Cosmetic may be potentiated (7) See 17 for PATIENT COUNSELING INFORMATION and

Medication Guide.

Revised: 07/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

FULL PRESCRIBING INFORMATION

WARNING: DISTANT SPREAD OF TOXIN EFFECT

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Instructions for Safe Use

2.2 Preparation and Dilution Technique

2.3 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Known Hypersensitivity to Botulinum Toxin

4.2 Infection at the Injection Site(s)

5 WARNINGS AND PRECAUTIONS

5.1 Lack of Interchangeability between Botulinum Toxin Products 5.2 Spread of Toxin Effect

5.3 Serious Adverse Reactions with Unapproved Use

5.4 Hypersensitivity Reactions

5.5 Cardiovascular System

5.6 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders

5.7 Dysphagia and Breathing Difficulties

6.2 Immunogenicity

6.3 Post-marketing Experience

7 DRUG INTERACTIONS

7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission

7.2 Anticholinergic Drugs

7.3 Other Botulinum Neurotoxin Products

7.4 Muscle Relaxants

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility WARNING: DISTANT SPREAD OF TOXIN EFFECT

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

5.8 Pre-existing Conditions at the Injection Site

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

5.10 Dry Eye in Patients Treated with BOTOX Cosmetic 5.11 Spatial Disorientation, Double Vision or Past-pointing in Patients Treated for Strabismus

5.12 Human Albumin and Transmission of Viral Diseases 6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

14 CLINICAL STUDIES

14.1 Glabellar Lines

14.2 Lateral Canthal Lines

14.3 Forehead Lines

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

WARNING: DISTANT SPREAD OF TOXIN EFFECT

Postmarketing reports indicate that the effects of BOTOX Cosmetic 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 and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and spasticity and at lower doses. [see Warnings and Precautions (5.2)]

1 INDICATIONS AND USAGE

BOTOX Cosmetic (onabotulinumtoxinA) is indicated in adult patients for the temporary improvement in the appearance of:

moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity

moderate to severe lateral canthal lines associated with orbicularis oculi activity

moderate to severe forehead lines associated with frontalis muscle activity 2 DOSAGE AND ADMINISTRATION

2.1 Instructions for Safe Use

The potency Units of BOTOX Cosmetic (onabotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX Cosmetic cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions (5.1) and Description (11)]. Indication specific dosage and administration recommendations should be followed. In treating adult patients for one or more indications with BOTOX and BOTOX Cosmetic, the maximum cumulative dose should generally not exceed 400 Units, in a 3 month interval.

The safety and effectiveness of dosing with BOTOX Cosmetic more frequently than every 3 months have not been clinically evaluated.

The safe and effective use of BOTOX Cosmetic depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. Physicians administering BOTOX Cosmetic must understand the relevant neuromuscular and structural anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures and disease. Do not use BOTOX Cosmetic and contact Allergan (1-800-***-****) if:

• The carton labeling does not contain an intact seal with a translucent silver Allergan logo (on both ends of the carton) or the seal has a black circle with a diagonal line through it (i.e., prohibition sign)

• The vial label does not contain a holographic film containing the name “Allergan” within rainbow-colored horizontal lines

• The U.S. License number 1145 is not present on the vial label and carton labeling [see How Supplied/Storage and Handling

(16)]

2.2 Preparation and Dilution Technique

BOTOX Cosmetic is supplied in single-dose 50 Units and 100 Units per vial. Prior to intramuscular injection, reconstitute each vacuum-dried vial of BOTOX Cosmetic with sterile, preservative-free 0.9% Sodium Chloride Injection USP (see Table 1). Draw up the proper amount of diluent in the appropriate size needle and syringe to obtain a reconstituted solution at a concentration of 4 Units/0.1 mL and a total treatment dose of 20 Units in 0.5 mL for glabellar lines, 24 Units in 0.6 mL for lateral canthal lines, and 40 Units in 1 mL for forehead lines and glabellar lines. Then slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix BOTOX Cosmetic with the saline by rotating the vial. Record the date and time of reconstitution on the space on the label. BOTOX Cosmetic should be administered within 24 hours after reconstitution. During this time period, reconstituted BOTOX Cosmetic should be stored in a refrigerator (2 to 8 C). BOTOX Cosmetic vials are for single-dose only. Discard any remaining solution.

Table 1: Dilution Instructions for BOTOX Cosmetic Vials (100 Units and 50 Units) Diluent* Added to

100 Unit Vial

Resulting Dose

Units per 0.1 mL

Diluent* Added to

50 Unit Vial

Resulting Dose

Units per 0.1 mL

2.5 mL 4 Units 1.25 mL 4 Units

*Preservative-free 0.9% Sodium Chloride Injection, USP Only Reconstituted BOTOX Cosmetic should be clear, colorless, and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit. Do not freeze reconstituted BOTOX Cosmetic.

2.3 Administration

Draw at least 0.5 mL (for glabellar lines), 0.6 mL (for lateral canthal lines), or 1 mL (for forehead lines treated in conjunction with glabellar lines) of the properly reconstituted toxin into the sterile syringe, preferably a tuberculin syringe and expel any air bubbles in the syringe barrel. Remove the needle used to reconstitute the product and attach a 30-33 gauge needle. Confirm the patency of the needle.

Glabellar Lines

Glabellar facial lines arise from the activity of the corrugator and orbicularis oculi muscles. These muscles move the brow medially, and the procerus and depressor supercilii pull the brow inferiorly. This creates a frown or “furrowed brow”. The location, size, and use of the muscles vary markedly among individuals. Lines induced by facial expression occur perpendicular to the direction of action of contracting facial muscles. An effective dose for facial lines is determined by gross observation of the patient’s ability to activate the superficial muscles injected.

In order to reduce the complication of ptosis the following steps should be taken:

• Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes.

• Lateral corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.

• Ensure the injected volume/dose is accurate and where feasible kept to a minimum.

• Do not inject toxin closer than 1 cm above the central eyebrow. Inject 4 Units (0.1 mL) of reconstituted BOTOX Cosmetic intramuscularly into each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a total dose of 20 Units (see Figure 1). Typically the initial doses of reconstituted BOTOX Cosmetic induce chemical denervation of the injected muscles one to two days after injection, increasing in intensity during the first week. The duration of effect of BOTOX Cosmetic for glabellar lines is approximately 3-4 months. Figure 1:

Lateral Canthal Lines

Lateral canthal lines arise largely from the activity of the orbicularis oculi muscles around the eye responsible for blinking and eyelid closure. Forceful contraction of the orbicularis oculi results in lateral and radially oriented folds (crow’s feet lines) which originate from the lateral canthus. The distribution of these radial lines differs among patients. Injections should be given with the needle bevel tip up and oriented away from the eye. Inject 4 Units/0.1 mL of reconstituted BOTOX Cosmetic into 3 sites per side (6 total injection points) in the lateral orbicularis oculi muscle for a total of 24 Units/0.6 mL

(12 Units per side). The first injection (A) should be approximately 1.5-2.0 cm temporal to the lateral canthus and just temporal to the orbital rim. If the lines in the lateral canthal region are above and below the lateral canthus, inject per Figure 2. Alternatively, if the lines in the lateral canthal region are primarily below the lateral canthus, inject per Figure 3. Figure 2: Figure 3:

For simultaneous treatment with glabellar lines, the dose is 24 Units for lateral canthal lines and 20 Units for glabellar lines (see Glabellar Lines Administration and Figure 1), with a total dose of 44 Units. Forehead Lines

Forehead lines arise largely from the activity of the frontalis muscles. This muscle moves the brow superiorly, interacting with the procerus, orbicularis, corrugator, and depressor supercilli. Frontalis contraction causes brow elevation. The location, size, and use of the muscles vary markedly among individuals.

Treat forehead lines in conjunction with glabellar lines (see Glabellar Lines Administration and Figure 1) to minimize the potential for brow ptosis. The recommended total dose for treatment of forehead lines (20 Units [0.5 mL]) in conjunction with glabellar lines (20 Units [0.5 mL]) is 40 Units (1mL).

When identifying the location of the appropriate injection sites in the frontalis muscle, assess the overall relationship between the size of the subject’s forehead, and the distribution of frontalis muscle activity. Locate the following horizontal treatment rows by light palpation of the forehead at rest and maximum eyebrow elevation:

Superior Margin of Frontalis Activity: approximately 1 cm above the most superior forehead crease

Lower Treatment Row: midway between the superior margin of frontalis activity and the eyebrow, at least 2 cm above the eyebrow

Upper Treatment Row: midway between the superior margin of frontalis activity and lower treatment row Inject 4 Units (0.1 mL) of reconstituted BOTOX Cosmetic into 5 sites in the frontalis muscle, for a total of 20 Units (0.5 mL). Place the 5 injections at the intersection of the horizontal treatment rows with the following vertical landmarks (see Figure 4):

On the lower treatment row at the midline of the face, and 0.5 – 1.5 cm medial to the palpated temporal fusion line (temporal crest); repeat for the other side.

On the upper treatment row, midway between the lateral and medial sites on the lower treatment row; repeat for the other side.

Figure 4:

For simultaneous treatment with lateral canthal lines, the total dose is 64 Units, comprised of 20 Units for forehead lines, 20 Units for glabellar lines, and 24 Units for lateral canthal lines (see Lateral Canthal Lines Administration and Figures 2 and 3). 3 DOSAGE FORMS AND STRENGTHS

For injection: 50 Units, vacuum-dried powder in a single-dose vial for reconstitution

For injection: 100 Units, vacuum-dried powder in a single-dose vial for reconstitution 4 CONTRAINDICATIONS

4.1 Known Hypersensitivity to Botulinum Toxin

BOTOX Cosmetic is contraindicated in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see Warnings and Precautions (5.4)]. 4.2 Infection at the Injection Site(s)

BOTOX Cosmetic is contraindicated in the presence of infection at the proposed injection site(s). 5 WARNINGS AND PRECAUTIONS

5.1 Lack of Interchangeability between Botulinum Toxin Products The potency Units of BOTOX Cosmetic are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX Cosmetic cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see Description (11)]. 5.2 Spread of Toxin Effect

Postmarketing safety data from BOTOX Cosmetic and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and 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 related to spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, and particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia and spasticity. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders occur. No definitive serious adverse event reports of distant spread of toxin effect associated with dermatologic use of BOTOX/BOTOX Cosmetic at the labeled dose of 20 Units (for glabellar lines), 24 Units (for lateral canthal lines), 40 Units (for forehead lines with glabellar lines), 44 Units (for simultaneous treatment of lateral canthal lines and glabellar lines), 64 Units (for simultaneous treatment of lateral canthal lines, glabellar lines, and forehead lines), or 100 Units (for severe primary axillary hyperhidrosis) have been reported.

No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX for blepharospasm at the recommended dose (30 Units and below), strabismus, or chronic migraine at the labeled doses have been reported. 5.3 Serious Adverse Reactions with Unapproved Use

Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with 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. 5.4 Hypersensitivity Reactions

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 injection of BOTOX Cosmetic should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined. 5.5 Cardiovascular System

There have been reports following administration of BOTOX/BOTOX Cosmetic of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease. Use caution when administering to patients with pre-existing cardiovascular disease. 5.6 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from onabotulinumtoxinA [see Warnings and Precautions (5.2, 5.7)]. 5.7 Dysphagia and Breathing Difficulties

Treatment with BOTOX and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre- existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening 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)].

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 tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised. Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been postmarketing reports of serious breathing difficulties, including respiratory failure. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscle for the treatment of cervical dystonia have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia. Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Warnings and Precautions (5.2)].

5.8 Pre-existing Conditions at the Injection Site

Caution should be used when BOTOX Cosmetic treatment is used in the presence of inflammation at the proposed injection site(s), ptosis, or when excessive weakness or atrophy is present in the targeted muscle(s). 5.9 Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm Reduced blinking from injection of botulinum toxin products in or near the orbicularis oculi muscle can lead to corneal exposure, persistent corneal epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Vigorous treatment of any corneal epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. 5.10 Dry Eye in Patients Treated with BOTOX Cosmetic There have been reports of dry eye associated with BOTOX Cosmetic injection in or near the orbicularis oculi muscle. If symptoms of dry eye (e.g., eye irritation, photophobia, or visual changes) persist, consider referring patients to an ophthalmologist [see Warnings and Precautions (5.9)].

5.11 Spatial Disorientation, Double Vision or Past-pointing in Patients Treated for Strabismus Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past pointing. Covering the affected eye may alleviate these symptoms.

5.12 Human Albumin and Transmission of Viral Diseases This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products. 6 ADVERSE REACTIONS

The following adverse reactions to BOTOX Cosmetic (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 (5.7)] 6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, but have different labeled Indications and Usage. Therefore, adverse events observed with the use of BOTOX also have the potential to be observed with the use of BOTOX Cosmetic.

In general, adverse reactions occur within the first week following injection of BOTOX Cosmetic and while generally transient, may have a duration of several months or longer. Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising may be associated with the injection. Needle-related pain and/or anxiety may result in vasovagal responses

(including e.g., syncope, hypotension), which may require appropriate medical therapy. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of nearby muscles may also occur due to spread of toxin [see Warnings and Precautions (5.2)]. Glabellar Lines

Table 2 lists selected adverse reactions reported by >1% of BOTOX Cosmetic treated subjects (N=405) aged 18 to 75 who were evaluated in the randomized, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of glabellar lines.

Table 2: Adverse Reactions Reported by >1% of BOTOX Cosmetic treated Subjects and More Frequent than in Placebo- treated Subjects in Double-blind, Placebo-controlled Clinical Studies of Treatment of Glabellar Lines Adverse Reactions by System Organ Class BOTOX Cosmetic

(N=405)

Placebo

(N=130)

General Disorders and Administration Site Conditions Facial pain

6 (1%)

0 (0%)

Nervous System Disorders

Facial paresis

5 (1%)

0 (0%)

Eye Disorders

Eyelid ptosis

13 (3%)

0 (0%)

Musculoskeletal and Connective Tissue Disorders

Muscular Weakness

6 (1%)

0 (0%)

Lateral Canthal Lines

Table 3 lists selected adverse reactions reported within 90 days following injection by >1% of BOTOX Cosmetic treated subjects

(N=526) aged 18 to 75 who were evaluated in two randomized, double-blind, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of lateral canthal lines alone. Table 3: Adverse Reaction Reported by 1% of BOTOX Cosmetic treated Subjects and More Frequent than in Placebo- treated Subjects Within 90 Days, in Double-blind, Placebo-controlled Clinical Studies of Treatment of Lateral Canthal Lines Adverse Reactions by System Organ Class BOTOX Cosmetic 24 Units

(N=526)

Placebo

(N=530)

Eye disorders

Eyelid edema

5 (1%)

0 (0%)

Forehead Lines

Table 4 lists selected adverse reactions reported by >1% of BOTOX Cosmetic treated subjects (N=665) aged 18 to 77 who were evaluated in two randomized, double-blind, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of forehead lines with glabellar lines. Table 4: Adverse Reactions Reported by 1% of BOTOX Cosmetic treated Subjects and More Frequent than in Placebo- treated Subjects, in Double-blind, Placebo-controlled Clinical Studies of Treatment of Forehead Lines Adverse Reactions by System Organ Class BOTOX Cosmetic

(20 Units forehead lines

with 20 Units glabellar lines)

(N=665)

Placebo

(N=

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