Botox Cosmetic Drug Information

Generic name: ONABOTULINUMTOXINA

Acetylcholine Release Inhibitor [EPC] Neuromuscular Blocker [EPC]

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Uses of Botox Cosmetic

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

Dosage & Administration of Botox Cosmetic

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

Side Effects of Botox Cosmetic

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 . 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 . 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)

Warnings & Cautions for Botox Cosmetic

Lack of Equivalency B etween Botulinum Toxin Products

The potency Units of BOTOX Cosmetic 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 .

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.

Advise patients or caregivers 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.

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.

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, discontinue further injection of BOTOX Cosmetic and immediately institute appropriate medical therapy. 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.

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.

Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders 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 . Monitor individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) when given botulinum toxin.

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 . 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 .

Pre-existing Conditions at the Injection Site Use caution 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).

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. Employ vigorous treatment of any corneal epithelial defect. 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 . 5. 1 1 Spatial Disorientation, Double Vision or Past- P ointing 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 a 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), which would also be considered 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.

Drug Interactions with Botox Cosmetic

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.

Anticholinergic Drugs Use of anticholinergic drugs after administration of

BOTOX Cosmetic may potentiate systemic anticholinergic effects.

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.

Muscle Relaxants Excessive weakness may also be exaggerated by administration of a

muscle relaxant before or after administration of BOTOX Cosmetic.

Pregnancy Safety for Botox Cosmetic

Units/kg) daily during the period of organogenesis (total of 12 doses in

rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the two highest doses in rats and 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-effect doses in these studies of 1 Unit/kg in rats is approximately equal the average high human dose of 64 Units based on Units/kg, and the developmental no-effect dose of 0.25 Units/kg in rabbits is less than the average high human dose based on Units/kg.

When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three different periods of development (prior to implantation, implantation, or organogenesis), no adverse effects on fetal development were observed. The developmental no-effect level for a single maternal dose in rats (16 Units/kg) is approximately 16 times the average high human dose of 64 Units based on Units/kg.

Pediatric Use of Botox Cosmetic

Pediatric Use The safety and effectiveness of BOTOX Cosmetic have not been established in pediatric patients.

Contraindications for Botox Cosmetic

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 .

Infection at the Injection Site(s)

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

Overdosage Information for Botox Cosmetic

Excessive doses of BOTOX Cosmetic (onabotulinumtoxinA) for injection may be expected to produce neuromuscular weakness with a variety of symptoms. Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection or oral ingestion occur or overdose be suspected, consider patients for further medical evaluation and immediately institute appropriate medical therapy, which may include hospitalization.

The patient should be medically supervised for several weeks for signs and symptoms of systemic muscular weakness which could be local, or distant from the site of injection . If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care.

In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 1-770-488-7100. More information can be obtained at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm.

Clinical Studies of Botox Cosmetic

Glabellar Lines Two randomized, multi-center, double-blind, placebo-controlled studies of identical design were

conducted to evaluate BOTOX Cosmetic for use in the temporary improvement of the appearance of moderate to severe glabellar facial lines. The studies enrolled healthy adults (ages 18 to 75) with glabellar lines of at least moderate severity at maximum frown. Subjects were excluded if they had ptosis, deep dermal scarring, or an inability to substantially lessen glabellar lines even by physically spreading them apart.

Subjects received a single treatment with BOTOX Cosmetic (N=405, combined studies) or placebo (N=132, combined studies). Injection volume was 0.1 mL/injection site, for a dose/injection site in the active treatment groups of 4 Units. Subjects were injected intramuscularly in five sites, 1 in the procerus muscle and 2 in each corrugator supercilii muscle, for a total dose in the active treatment groups of 20 Units. The co-primary efficacy endpoints were the investigator’s rating of glabellar line severity at maximum frown and the subject’s global assessment of change in appearance of glabellar lines, both at Day 30 post-injection.

For the investigator rating, using a 4-point grading scale (0=none, 3=severe) a responder was defined as having a severity grade of 0 or 1. For the subject’s global assessment of change, the ratings were from +4 (complete improvement) to -4 (very marked worsening). A responder was defined as having a grade of at least +2 (moderate improvement). After completion of the randomized studies, subjects were offered participation in an open label, repeat treatment study to assess the safety of repeated treatment sessions. The combined results of these two efficacy studies are presented here. The mean age was 46 years, with 32 subjects (6%) ≥65 years of age.

Most of the subjects were women (82%), and White (84%). At baseline, 210 subjects (39%) had glabellar line severity scores at rest of moderate or severe. In these studies, the severity of glabellar lines was reduced for up to 120 days in the BOTOX Cosmetic group compared to the placebo group as measured both by investigator rating of glabellar line severity at maximum frown (Table 8), and by subject’s global assessment of change in appearance of glabellar lines (Table 9). Table 8: Investigator’s Assessment of Glabellar Line Severity at Maximum Frown – Responder Rates (% and Number of Subjects with Severity of None or Mild) Day BOTOX Cosmetic Placebo Difference a 7 74% 299/405 6% 8/132 68% 30 b 80% 325/405 3% 4/132 77% 60 70% 283/403 2% 2/130 69% 90 48% 192/403 2% 3/128 45% 120 25% 102/403 2% 2/128 24% a 95% confidence intervals are shown in parenthesis b Day 30: Co-Primary Efficacy Time point, p<0.001 Table 9: Subject’s Assessment of Change in Appearance of Glabellar Lines – Responder Rates (% and Number of Subjects with at Least Moderate Improvement) Day BOTOX Cosmetic Placebo Difference a 7 82% 334/405 9% 12/132 73% 30 b 89% 362/405 7% 9/132 83% 60 82% 330/403 4% 5/130 78% 90 63% 254/403 3% 4/128 60% 120 39% 157/403 1% 1/128 38% a 95% confidence intervals are shown in parenthesis b Day 30: Co-Primary Efficacy Time point, p<0.001 In the subset of subjects with resting severity scores of moderate or severe, the investigator assessment of a resting severity of mild or none at Day 30 was also achieved by more BOTOX Cosmetic treated subjects (74%, 119/161) than placebo treated subjects (20%, 10/49). Analysis of the limited number of subjects 65 years or older suggested a lower treatment-associated response compared to subjects less than 65 years of age (Table 10). Table 10: Investigator’s and Subject’s Assessment – Responder Rates for Subjects <65 and ≥65 Years of Age at Day 30 Assessment Age Group BOTOX Cosmetic (N=405) Placebo (N=132) Difference a Investigators (maximal frown) <65 83% 316/382 2% 2/123 81% Subjects <65 91% 346/382 7% 8/123 84% Investigators (maximal frown) ≥65 39% 9/23 22% 2/9 17% (-17, 51) Subjects ≥65 70% 16/23 11% 1/9 58% a 95% confidence intervals are shown in parenthesis Exploratory analyses by gender suggested that responder rates in the BOTOX Cosmetic treated group were higher for women than for men for both the investigator assessment (Day 30; 85% of 334 women, 59% of 71 men) and the Subject Assessment (Day 30; 93% of women, 72% of men). In the limited number of subjects that identified as other races (n=64 in the BOTOX Cosmetic treated group) the responder rates were similar to those observed in White subjects.

Lateral Canthal Lines Two multicenter, randomized, double-blind, placebo-controlled studies evaluated

BOTOX Cosmetic (N=833, randomized to receive any BOTOX Cosmetic treatment or N=529 randomized to receive placebo) for the temporary improvement in the appearance of moderate to severe lateral canthal lines (LCL). Study 1 assessed BOTOX Cosmetic treatment of LCL alone; Study 2 also assessed simultaneous treatment of LCL and glabellar lines (GL). Both studies enrolled healthy adults with moderate to severe LCL at maximum smile at baseline; Study 2 also required subjects to have moderate to severe GL at maximum frown at baseline. In the 5-month Study 1, subjects were randomized to receive a single blinded treatment of 24 Units/0.6 mL (12 Units per side) consisting of 4 Units/0.1 mL into 3 sites of each orbicularis oculi muscle with either BOTOX Cosmetic (N=222) or placebo (N=223). In the 7-month Study 2, subjects were randomized to receive either BOTOX Cosmetic in the LCL region and placebo in the GL region (24 Units; N=306), or BOTOX Cosmetic in the LCL and GL regions (44 Units ; N=305), or placebo in the LCL and GL regions (0 Units; N=306). Subjects received the same 24 Units regimen for LCL as in Study 1, and the labeled 20 Units (5 injections, 4 Units per site) for GL. Subjects received the same treatment at days 1 and 120. The primary efficacy measure was the assessment of LCL severity at maximum smile using the 4-point Facial Wrinkle Scale with Photonumeric Guide (FWS; 0=none, 1= mild, 2=moderate, 3=severe). The FWS assessment was performed independently by both investigators and subjects. The primary timepoint was day 30 following the first treatment, as compared to baseline.

The primary efficacy response definition was a composite ≥2-grade improvement from baseline in LCL severity at maximum smile, assessed by both investigator and subject on a per-subject basis. For Studies 1 and 2, the proportion of responders was statistically significant favoring BOTOX Cosmetic (24 Units and 44 Units ) compared to placebo at day 30 (Table 11). Table 11: Studies 1 and 2: Composite Investigator and Subject Assessment of LCL at Maximum Smile at Day 30 – Responder Rates (% and Number of Subjects Achieving ≥2-Grade Improvement from Baseline) Study BOTOX Cosmetic 24 Units BOTOX Cosmetic 24 Units LCL and 20 Units GL Placebo Study 1 26.1% 58/222 - 1.3% 3/223 Study 2 20.3% 62/306 21.3% 65/305 0.0% 0/306 The secondary endpoint of a responder defined as achieving a grade of none or mild for Study 1 as measured by the investigator is presented in Figure 7 below. Figure 7 : Percentage of Subjects with Treatment Success (% of Subjects achieving None or Mild from Baseline) by Visit (Study 1)

Forehead Lines Two multicenter, randomized, double-blind, placebo-controlled studies evaluated

BOTOX Cosmetic (N=921, randomized to receive any BOTOX Cosmetic treatment or N=257, randomized to receive placebo) for the temporary improvement in the appearance of moderate to severe forehead lines (FHL). Study 1 assessed BOTOX Cosmetic treatment of FHL with glabellar lines (GL); Study 2 also assessed simultaneous treatment of FHL, GL, and lateral canthal lines. Both studies enrolled healthy adults with moderate to severe FHL at maximum eyebrow elevation at baseline and moderate to severe GL at maximum frown at baseline; Study 2 also required subjects to have moderate to severe LCL at maximum smile at baseline. In the 12-month Study 1, subjects were randomized to receive BOTOX Cosmetic 20 Units to the frontalis muscle with 20 Units to the glabellar region (for a total of 40 Units) or placebo in both areas.

In the 12-month Study 2, subjects were randomized to receive BOTOX Cosmetic 20 Units to the frontalis muscle, 20 Units to the glabellar region, and 0 Units to the LCL region (for a total of 40 units) or BOTOX Cosmetic 20 Units to the frontalis muscle, 20 Units to the glabellar region, and 24 Units to the LCL region (for a total of 64 Units) or placebo in all three areas. The primary efficacy measure was the assessment of FHL severity at maximum eyebrow elevation using the 4-point Facial Wrinkle Scale with Photonumeric Guide (FWS; 0=none, 1= mild, 2=moderate, 3=severe). The FWS assessment was performed independently by both investigators and subjects. The primary timepoint was Day 30 following the first treatment.

The primary efficacy response definition was a composite ≥2-grade improvement from baseline in FHL severity at maximum eyebrow elevation, assessed by both investigator and subject on a per-subject basis. For Studies 1 and 2, the proportion of responders was greater in the BOTOX Cosmetic arms compared to placebo at Day 30 (p<0.0001 for Studies 1 and 2) (Table 12). Table 12: Studies 1 and 2: Composite Investigator and Subject Assessment of FHL Severity at Maximum Eyebrow Elevation at Day 30 – Responder Rates (% and Number of Subjects Achieving ≥2-Grade Improvement from Baseline) Study BOTOX Cosmetic (20 Units FHL with 20 Units GL) BOTOX Cosmetic (20 Units FHL, 20 Units GL, and 24 Units LCL) Placebo Study 1 N=290 61% - N=101 0% Study 2 N=318 46% N=313 53% N=156 1% A total of 165 and 197 subjects received 3 cycles over 1 year of BOTOX Cosmetic 40 Units (20 Units FHL with 20 Units GL) and 64 Units (20 Units FHL, 20 Units GL, and 24 Units LCL), respectively. The response rate for FHL was similar across all treatment cycles.

The results for a key secondary endpoint of responders achieving a grade of none or mild on investigator ratings at maximum eyebrow elevation of FHL severity are presented below for Studies 1 and 2. Figure 8 : Percentage of Subjects with Treatment Success ( A chieving None or Mild FHL from Baseline at Maximum Eyebrow Elevation ) by Visit (Study 1) Figure 9 : Percentage of Subjects with Treatment Success ( A chieving None or Mild FHL from Baseline at Maximum Eyebrow Elevation ) by Visit (Study 2) The results of the Facial Line Satisfaction Questionnaire are presented in Table 13. Table 13: Facial Lines Satisfaction Questionnaire Response Frequency at Day 60 (Percentage of Subjects) Study 1 Study 2 BOTOX Cosmetic (20 Units FHL with 20 Units GL) N=289 Placebo N=99 BOTOX Cosmetic (20 Units FHL with 20 Units GL) N=317 Placebo N=155 “Very satisfied” 57% 1% 35% 0% “Mostly satisfied” 33% 0% 47% 3% “Neither dissatisfied nor satisfied” 4% 22% 9% 23% “Mostly dissatisfied” 4% 21% 7% 20% “Very dissatisfied” 2% 56% 2% 54%

Platysma Bands Two multicenter, randomized, double-blind, placebo-controlled trials (Study M21-309 and Study

M21-310 ) evaluated BOTOX Cosmetic (N=408 BOTOX Cosmetic and N=426 placebo) for the temporary improvement in the appearance of moderate to severe platysma bands. Based on baseline severity, subjects were randomized to receive a single treatment of BOTOX Cosmetic (26 Units, 31 Units, or 36 Units), or placebo. The primary efficacy measure was the assessment of platysma band severity at maximum contraction using the 5-grade clinician platysma band scale by the investigators, and the 5-grade participant platysma band scale by the subjects.

For both scales, the 5 grades are 1=Minimal, 2=Mild, 3=Moderate, 4=Severe, 5=Extreme (Table 14). The investigator and subject assessments were performed independently. Table 14: Platysma Band Severity Grades and Descriptions Grade Severity Description 1 Minimal; no visible neck bands and no impact to jawline definition 2 Mild; visible neck bands and no impact to jawline definition 3 Moderate; 1 visible continuous neck band impacting jawline definition 4 Severe; 2 visible continuous neck bands impacting jawline definition 5 Extreme; 3 or more visible neck bands impacting jawline definition The primary timepoint was Day 14 after the first treatment. The studies enrolled healthy adults with moderate to severe platysma bands.

In these studies, 94% were female, 91% were White, 5% were Asian, 3% were Black or African American; for ethnicity, 86% identified as not Hispanic or Latino. Subjects were 19 to 82 years old, with a mean age of 49 years. The primary efficacy endpoint was a multi-component endpoint defined as achievement of Grade 1 or 2 (Minimal or Mild) and at least a 2-grade improvement from baseline in platysma band severity at maximum contraction, assessed by both investigator and subject at Day 14 (Table 15). Table 15: Studies M21-309 and M21-310: Percentage of Subjects Achieving a Grade 1 or 2 (Minimal or Mild) with ≥ 2-Grade Improvement from Baseline Based on Both Investigator and Subject Assessments of Platysma Band Severity at Maximum Contraction at Day 14 Study M21-309 Study M21-310 BOTOX Cosmetic 26, 31, or 36 Units (N=199) Placebo (N=209) Difference d BOTOX Cosmetic 26, 31, or 36 Units (N=209) Placebo (N=217) Difference d Multi-component Assessment a 32% 2% 30% (24%, 37%) 31% 0% 31% (24%, 37%) Individual Components Investigator Assessment b 45% 4% - 42% 2% - Subject Assessment c 44% 4% - 40% 3% - Grade 1 or 2 (Minimal or Mild) and ≥ 2-grade improvement from baseline at maximum contraction on both the investigator and subject assessments at Day 14. Grade 1 or 2 (Minimal or Mild) and ≥ 2-grade improvement from baseline at maximum contraction on the investigator assessment at Day 14. Grade 1 or 2 (Minimal or Mild) and ≥ 2-grade improvement from baseline at maximum contraction on the subject assessment at Day 14. 95% confidence intervals are shown in parentheses.

The percentages of subjects achieving these endpoints over time are shown in Figure 10 (Study M21-309) and Figure 11 (Study M21-310). Figure 10 : Percentages of Subjects Achieving a Grade 1 or 2 (Minimal or Mild) and at Least 2-Grade Improvement from Baseline Based on Both the Investigator and Subject Assessments of Platysma Band Severity at Maximum Contraction Over Time (Study M21-309) Figure 11 : Percentages of Subjects Achieving a Grade 1 or 2 (Minimal or Mild) and at Least 2-Grade Improvement from Baseline Based on Both the Investigator and Subject Assessments of Platysma Band Severity at Maximum Contraction Over Time (Study M21-310) The results for Appearance of Neck and Lower Face Questionnaire: Satisfaction (Follow-up) Item 5 at Day 14 secondary efficacy endpoints are presented for Studies M21-309 and M21-310 in Table 16. Table 16: Studies M21-309 and M21-310: Results for Appearance of Neck and Lower Face Questionnaire: Satisfaction (Follow-up) Item 5 (Satisfaction with Effect of Treatment on Platysma Bands) at Day 14 (Percentage of Subjects) Responses Study M21-309 Study M21-310 BOTOX Cosmetic 26, 31, or 36 Units (N = 199) Placebo (N = 209) BOTOX Cosmetic 26, 31, or 36 Units (N = 209) Placebo (N = 217) “Very satisfied” 31% 3% 22% 2% “Satisfied” 34% 9% 40% 10% “Neither satisfied nor dissatisfied” 25% 31% 25% 32% “Dissatisfied” 7% 34% 10% 29% “Very dissatisfied” 2% 24% 3% 27%

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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