BOTOX COSMETIC

BOTOX Cosmetic (onabotulinumtoxinA) for injection, is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A intended for intramuscular use. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying. The primary release procedure for BOTOX Cosmetic uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to AbbVie’s products BOTOX and BOTOX Cosmetic. One Unit of BOTOX Cosmetic corresponds to the calculated median intraperitoneal lethal dose (LD 50 ) in mice. Due to specific details of this assay such as the vehicle, dilution scheme and laboratory protocols, Units of biological activity of BOTOX Cosmetic 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 Cosmetic is approximately 20 Units/nanogram of neurotoxin complex. Each vial of BOTOX Cosmetic contains either 50 Units of Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of sodium chloride; or 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.

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 • moderate to severe platysma bands associated with platysma muscle activity 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 Moderate to severe platysma bands associated with platysma muscle activity

Glabellar Lines Administration: 0.1 mL (4 Units) into each of 5 sites, for a total dose of 20 Units ( 2.4 ) 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 ( 2.4 ) 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 ( 2.4 ) Platysma Bands Administration: 0.05 mL (2 Units) into each of 4 sites in the upper segment of the platysma muscles, below the jawline on each side and 0.025 mL (1 Unit) into 5 sites on each vertical neck band per side (1 to 2 bands per side) for a total of 26 Units, 31 Units, or 36 Units (18, 23, or 28 injection sites, respectively) ( 2.4 ) BOTOX Cosmetic is administered by intramuscular injection ( 2.2 ) Follow dosage and administration recommendations. Do not exceed the maximum recommended cumulative dose in a treatment session for any indication ( 2.1 , 2.2 ) See Preparation and Reconstitution Instructions for information on BOTOX Cosmetic reconstitution, storage, and preparation before injection ( 2.3 ) Figure 1: Figure 2 and 3 Figure 4: Figure 5: Injection Sites for Platysma Prominence (2 Bands) Figure 6: Injection Sites for Platysma Prominence (1 Band) 2.1 Instructions for Safe Use The potency Units of BOTOX Cosmetic (onabotulinumtoxinA) for injection are specific to the preparation and assay method utilized. BOTOX Cosmetic is not equivalent to 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 )] . Follow indication specific dosage and administration recommendations. Do not exceed the maximum recommended cumulative dose in a treatment session for any indication. 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 AbbVie (1-800-678-1605) if: The tamper evident features on the carton appear to be broken or compromised, or The U.S. License number 1889 is not present on the vial label and carton labeling [see How Supplied/Storage and Handling ( 16 )] 2.2 Recommended Dose The total recommended dose in adult patients by treatment area is shown in Table 1. BOTOX Cosmetic is administered by intramuscular injection. Table 1: Total Recommended Treatment Dose Treatment Area Total Recommended Treatment Dose Glabellar lines 20 Units in 0.5 mL Lateral canthal lines 24 Units in 0.6 mL Forehead lines and glabellar lines 40 Units in 1 mL Platysma bands One band on each side: 26 Units in 0.65 mL 1 band on one side, 2 bands on the other side: 31 Units in 0.78 mL Two bands on each side: 36 Units in 0.9 mL The safety and effectiveness of dosing with BOTOX Cosmetic more frequently than every 3 months have not been clinically evaluated. 2.3 Preparation and Reconstitution Instructions 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 2). 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. Table 2: Dilution Instructions for BOTOX Cosmetic Vials (50 Units and 100 Units) Vial Amount of Diluent* Added Resulting Dose Units per 0.1 mL 50 Units 1.25 mL 4 Units 100 Units 2.5 mL 4 Units *Preservative-free 0.9% Sodium Chloride Injection, USP Only 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. Administer BOTOX Cosmetic within 24 hours after reconstitution. During this time period, store reconstituted BOTOX Cosmetic in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze reconstituted BOTOX Cosmetic. BOTOX Cosmetic vials are for single-dose only. Discard any remaining solution. Reconstituted BOTOX Cosmetic is clear, colorless to slightly yellow solution, 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 use if the solution is cloudy or contains flakes or particles. 2. 4 Administration Draw properly reconstituted toxin into the sterile syringe, preferably a tuberculin syringe, and expel any air bubbles in the syringe barrel (see Table 3). Remove the needle used to reconstitute the product and attach a 30-33 gauge needle. Confirm the patency of the needle. Table 3: Amount of Reconstituted Toxin to Draw Per Treatment Area Treatment Area Amount of Reconstituted Toxin to Draw Glabellar lines At least 0.5 mL Lateral canthal lines At least 0.6 mL Forehead lines and glabellar lines At least 1 mL Platysma bands 1 band on each side: At least 0.65 mL 1 band on one side, 2 bands on the other side: At least 0.78 mL 2 bands on each side: At least 0.9 mL Glabellar Lines 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, take the following steps: Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. Place lateral corrugator injections 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 Give injections 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). Administer the first injection (A) 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. 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 in Conjunction with Glabellar Lines 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 (1 mL). 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). Platysma Bands Using an appropriately sized sterile syringe, needle, and aseptic technique, inject 2 Units (0.05 mL) of reconstituted BOTOX Cosmetic into 4 sites in the upper segment of platysma muscle, below the jawline on each side. For each side, administer the 4 jawline injections to the upper platysma muscle approximately 1 to 2 cm inferior and parallel to the lower mandibular border. Ensure the anterior injection site is in line with the oral commissure, and the posterior injection is slightly anterior to the angle of the mandible. Administer the remaining 2 injections equidistant (approximately 1 to 2 cm apart) between the anterior and posterior injection points (see Figures 5 and 6). In addition, inject 1 Unit (0.025 mL) of reconstituted BOTOX Cosmetic into 5 sites along each vertical neck band, 1 to 2 vertical neck bands per side. For each vertical neck band identified, 1 to 2 per side, distribute 5 injections vertically approximately 1 to 2 cm apart (see Figures 5 and 6). Ensure the most superior injection site is approximately 1 to 2 cm inferior to the jawline injections. Depending on platysma band severity, the total dose may be 26 Units (1 band/side), 31 Units (1 band one side, 2 bands other side), or 36 Units (2 bands/side) (see Table 4 and Figures 5 and 6 below). Figure 5 : Injection Sites for Platysma Band (2 Bands) Figure 6 : Injection Sites for Platysma Band (1 Band) Administer all platysma muscle injections superficially and intramuscularly with the needle perpendicular to the surface of the skin. For vertical neck band injections, identify each band while the patient is contracting their platysma. Gently pinch the band to isolate the muscle from nearby anatomical structures during administration (see Table 4). To reduce injection-related complications, administer injection at least 1 cm inferior to the lower mandibular border. Do not inject into structures deep to the platysma muscle, particularly in the anterior region of the neck. Table 4: Dosing for Platysma Bands Platysma Bands Presentation Jawline Injections Neck Band Injections Total Number of Injection Sites Total Dose 1 band on each side 2 Units (0.05 mL) into 4 sites per side (total of 8 sites and 16 Units) 1 Unit (0.025 mL) into 5 sites per band (total of 10 sites and 10 Units) 18 sites 26 Units (0.65 mL) 1 band on one side, 2 bands on the other side 2 Units (0.05 mL) into 4 sites per side (total of 8 sites and 16 Units) 1 Unit (0.025 mL) into 5 sites per band (total of 15 sites and 15 Units) 23 sites 31 Units (0.78 mL) 2 bands on each side 2 Units (0.05 mL) into 4 sites per side (total of 8 sites and 16 Units) 1 Unit (0.025 mL) into 5 sites per band (total of 20 sites and 20 Units) 28 sites 36 Units (0.9 mL)

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 ) 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).

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 )] 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 AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 in many cases are 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 5 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 5: 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 6 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 6: 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 7 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 7: Adverse Reactions Reported by ≥1% of BOTOX Cosmetic treated Subjects More Frequently 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=315) Nervous System Disorders Headache 58 (9%) 17 (5%) Eye Disorders Eyelid ptosis 12 (2%) 1 (0%) Skin and Subcutaneous Tissue Disorders Brow ptosis Skin tightness 13 (2%) 10 (2%) 0 (0%) 0 (0%) There were no additional adverse drug reactions reported with the simultaneous treatment of forehead lines, glabellar lines, and lateral canthal lines. Platysma Bands The safety of BOTOX Cosmetic (26 Units, 31 Units, or 36 Units) was evaluated in two double-blind, placebo-controlled, clinical trials with 407 BOTOX Cosmetic-treated subjects and 425 subjects receiving placebo. The safety profile of BOTOX Cosmetic treatment of platysma bands is consistent with the known safety profile of BOTOX Cosmetic for other indications. 6. 2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin [see Warnings and Precautions ( 5.4 , 5.7 )] . There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events. The following adverse reactions by System Organ Class have been identified during post-approval use of BOTOX/BOTOX Cosmetic: Ear and labyrinth disorders Hypoacusis; tinnitus; vertigo Eye disorders Diplopia; dry eye; eyelid edema; lagophthalmos; strabismus; visual disturbances; vision blurred Gastrointestinal disorders Abdominal pain; diarrhea; dry mouth; nausea; vomiting General disorders and administration site conditions Denervation; malaise; pyrexia Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Localized muscle twitching/involuntary muscle contractions; Mephisto sign; muscle atrophy; myalgia Nervous system disorders Brachial plexopathy; dysarthria; facial palsy; hypoaesthesia; localized numbness; myasthenia gravis; paresthesia; peripheral neuropathy; radiculopathy; syncope Respiratory, thoracic and mediastinal disorders Aspiration pneumonia; dyspnea; respiratory depression and/or respiratory failure Skin and subcutaneous tissue disorders Alopecia, including madarosis; hyperhidrosis; pruritus; skin rash (including erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption)

No formal drug interaction studies have been conducted with BOTOX Cosmetic (onabotulinumtoxinA) for injection. 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 ) 7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of BOTOX Cosmetic and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated. 7.2 Anticholinergic Drugs Use of anticholinergic drugs after administration of BOTOX Cosmetic may potentiate systemic anticholinergic effects. 7.3 Other Botulinum Neurotoxin Products The effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. 7.4 Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of BOTOX Cosmetic.