1 INDICATIONS AND USAGE XEOMIN is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the treatment or improvement of: Chronic sialorrhea in patients 2 years of age and older ( 1.1 ) Upper limb spasticity in adults ( 1.2 ) Upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy ( 1.2 ) Cervical dystonia in adults ( 1.3 ) Blepharospasm in adults ( 1.4 ) the appearance of upper facial lines in adults: moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity ( 1.5 ) moderate to severe horizontal forehead lines associated with frontalis muscle activity ( 1.5 ) moderate to severe lateral canthal lines associated with orbicularis oculi muscle activity ( 1.5 ) 1.1 Chronic Sialorrhea XEOMIN is indicated for the treatment of chronic sialorrhea in patients 2 years of age and older.

1.2 Upper Limb Spasticity Upper Limb Spasticity in Adult Patients XEOMIN is indicated for the treatment of upper limb spasticity in adult patients.

Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy XEOMIN is indicated for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy.

1.3 Cervical Dystonia XEOMIN is indicated for the treatment of cervical dystonia in adult patients.

1.4 Blepharospasm XEOMIN is indicated for the treatment of blepharospasm in adult patients.

1.5 Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines) XEOMIN is indicated in adult patients for the temporary improvement in the appearance of upper facial lines: moderate to severe glabellar lines (GL) associated with corrugator and/or procerus muscle activity moderate to severe horizontal forehead lines (HFL) associated with frontalis muscle activity moderate to severe lateral canthal lines (LCL) associated with orbicularis oculi muscle activity.

6 ADVERSE REACTIONS The following adverse reactions to XEOMIN are discussed in greater detail in other sections of the labeling: Spread of Effects from Toxin [see Warnings and Precautions (5.1) ] Lack of Unit Equivalency between Botulinum Toxin Products [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.4) ] Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated with XEOMIN for Blepharospasm [see Warnings and Precautions (5.5) ] Risk of Ptosis in Patients Treated for Glabellar Lines [see Warnings and Precautions (5.6) ] Human Albumin and Transmission of Viral Diseases [see Warnings and Precautions (5.7) ] The most commonly observed adverse reactions at rates specified below and greater than placebo are: Chronic Sialorrhea: Chronic Sialorrhea in Adults (≥4% of patients) : tooth extraction, dry mouth, diarrhea, and hypertension ( 6.1 ) Chronic Sialorrhea in Pediatric Patients (≥1% of patients): bronchitis, headache, and nausea/vomiting ( 6.1 ) Spasticity: Upper Limb Spasticity in Adults (≥2% of patients) : seizure, nasopharyngitis, dry mouth, and upper respiratory tract infection ( 6.1 ) Upper Limb Spasticity in Pediatric Patients (≥3% of patients) : nasopharyngitis and bronchitis ( 6.1 ) Cervical Dystonia (≥5% of patients) : dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain ( 6.1 ) Blepharospasm (≥10% of patients) : eyelid ptosis, dry eye, visual impairment, and dry mouth ( 6.1 ) Upper facial lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines): (>1% of patients) : injection site bruising ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 888-493-6646 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, 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 practice.

Chronic Sialorrhea Chronic Sialorrhea in Adult Patients Table 6 lists the adverse reactions that occurred in ≥3% of XEOMIN-treated patients in the double-blind, placebo-controlled phase of the study in adult patients with chronic sialorrhea [see Clinical Studies (14.1) ] .

The most common adverse reactions (≥4%) were tooth extraction, dry mouth, diarrhea, and hypertension.

In the controlled portion of this study, 74 patients received 100 Units of XEOMIN, and 36 patients received placebo.

XEOMIN-treated patients were 21-80 years old (mean 65 years), and were predominantly male (71%) and White (99.5%).

Table 6: Adverse Reactions (≥3%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Adult Chronic Sialorrhea Study Adverse Reaction XEOMIN 100 Units (N = 74) % Placebo (N = 36) % Tooth extraction 5 0 Dry mouth 4 0 Diarrhea 4 3 Hypertension 4 3 Fall 3 0 Bronchitis 3 0 Dysphonia 3 0 Back pain 3 0 Dry eye 3 0 Chronic Sialorrhea in Pediatric Patients Table 7 lists the adverse reactions that occurred in ≥1% of XEOMIN-treated patients 6-17 years of age in the double-blind, placebo-controlled portion of the study in pediatric patients with chronic sialorrhea [see Clinical Studies (14.1) ] .

Of the patients 6-17 years of age, 148 patients received a dose of XEOMIN according to body weight, and 72 patients received placebo.

Thirty-five patients 2-5 years of age received an open-label dose of XEOMIN according to body weight.

XEOMIN-treated patients were 2-17 years of age (mean 10 years), predominately male (63%) and White (100%).

Table 7: Adverse Reactions (≥1%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Pediatric Chronic Sialorrhea Study Adverse Reaction XEOMIN (6-17 years) (N = 148) % Placebo (6-17 years) (N = 72) % Bronchitis 1 0 Headache 1 0 Nausea/Vomiting 1 0 The most frequently reported adverse reaction in patients ages 2-5 years after XEOMIN injections was nasopharyngitis (6%).

In the open-label extension period, 222 patients 2-17 years of age received up to three additional treatments with XEOMIN every 16±2 weeks.

The safety profile of XEOMIN during the open-label extension period was similar to that observed in the double-blind phase of the placebo-controlled pediatric chronic sialorrhea study.

Upper Limb Spasticity Upper Limb Spasticity in Adult Patients Table 8 lists the adverse reactions that occurred in ≥2% of XEOMIN-treated patients in two placebo-controlled studies in adult patients with upper limb spasticity.

Study 1 and Study 2 were both double-blind, placebo-controlled studies, with an open-label extension [see Clinical Studies (14.2) ] .

In the controlled portion of these studies, 283 patients received ≥120 Units to 400 Units, of which 217 patients received at least 400 Units of XEOMIN, and 182 patients received placebo.

XEOMIN-treated patients were 20-79 years of age (mean 56 years), and were predominantly male (58%), and White (84%).

Table 8: Adverse Reactions (≥2%) and Greater for XEOMIN than Placebo: Double-Blind Phase of Placebo-Controlled Adult Upper Limb Spasticity Study 1 and Study 2 Adverse Reaction XEOMIN 400 Units (N = 217) % Placebo (N = 182) % Seizure 3 0 Nasopharyngitis 2 0 Dry mouth 2 1 Upper respiratory tract infection 2 1 Upper Limb Spasticity in Pediatric Patients Table 9 lists the adverse reactions that occurred in ≥2% of XEOMIN-treated patients in Study 1 in pediatric patients 2 years of age and older with upper limb spasticity.

In the controlled portion of Study 1, 350 patients were randomized to one of three doses of XEOMIN: 87 received 2 Units/kg per affected upper limb, 87 received 6 Units/kg per affected upper limb, and 176 received 8 Units/kg per affected upper limb [ see Clinical Studies (14.2) ] .

XEOMIN-treated patients were 2 to 17 years of age (mean 7 years), 63% were male, and 90% were White.

No relationship between increased dose and increased occurrence of adverse reactions was observed.

The most common adverse reactions (≥3% of XEOMIN-treated patients) at the recommended dose of XEOMIN (8 Units/kg) were nasopharyngitis and bronchitis.

Table 9: Adverse Reactions (≥2%) in Patients Treated with XEOMIN 2 Units/kg or 8 Units/kg: Double-Blind Phase of Study 1 in Pediatric Upper Limb Spasticity Adverse Reactions XEOMIN 2 Units/kg N=87 % XEOMIN 8 Units/kg N=176 % Infections and infestations Nasopharyngitis 6 3 Bronchitis 2 3 Pharyngotonsillitis Includes pharyngotonsillitis, pharyngitis and tonsillitis 2 2 Upper respiratory tract infection 2 2 Respiratory tract infection viral 1 2 Injury, poisoning and procedural complications Fall 0 2 Musculoskeletal and connective tissue disorders Pain in extremity 0 2 Cervical Dystonia The data described below reflect exposure to a single intramuscular dose of XEOMIN in a placebo-controlled, Phase 3 trial in patients with cervical dystonia [ see Clinical Studies (14.3) ].

In this study, 159 patients received XEOMIN (78 were randomized to receive a total dose of 120 Units, and 81 were randomized to receive a total dose of 240 Units).

XEOMIN-treated patients were 18 to 79 years old (mean 53 years), and were predominantly female (66%) and Caucasian (91%).

At study baseline, approximately 25% had mild, 50% had moderate, and 25% had severe cervical dystonia.

Approximately 61% of XEOMIN-treated patients had previously received another botulinum toxin type A product.

Table 10 lists adverse reactions that occurred in ≥5% of XEOMIN-treated patients (in any treatment group) and greater than placebo.

Table 10: Adverse Reactions (≥5%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Cervical Dystonia Study Adverse Reaction XEOMIN 120 Units (N=77) % XEOMIN 240 Units (N=82) % Placebo (N=74) % Musculoskeletal and connective tissue disorders 23 32 11 Neck pain 7 15 4 Muscular weakness 7 11 1 Musculoskeletal pain 7 4 1 Gastrointestinal disorders 18 24 4 Dysphagia 13 18 3 Nervous system disorders 16 17 7 General disorders and administration site conditions 16 11 11 Injection site pain 9 4 7 Infections and infestations 14 13 11 Respiratory, thoracic and mediastinal disorders 13 10 3 Blepharospasm Study 1 was a randomized, double-blind, placebo-controlled study that only included treatment-naïve patients [see Clinical Studies (14.4) ] .

In the controlled portion, 22 patients received XEOMIN 25 Units, 19 patients received 50 Units, and 20 patients received placebo.

XEOMIN-treated patients were 23 to 78 years of age (mean 55 years).

Fifty-nine percent of the patients were women, 77% were Asian, and 23% White.

No patients withdrew prematurely because of an adverse event.

Table 11 lists the adverse reactions that occurred in ≥6% of XEOMIN-treated patients and greater than placebo.

Table 11: Adverse Reactions (≥6%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Blepharospasm Study 1 Adverse Reaction XEOMIN 50 U (N=19) % Placebo (N=20) % Eye disorders 21 10 Eyelid ptosis 16 0 Study 2 was a double-blind, placebo-controlled, flexible dose study with an open-label extension (OLEX) period.

The study only included patients previously treated with onabotulinumtoxinA (Botox) [see Clinical Studies (14.4) ] .

In the controlled portion, 74 patients received XEOMIN at a mean dose of approximately 33 Units per eye (minimum 10 Units, maximum 50 Units).

XEOMIN-treated patients were 22 to 79 years of age (mean 62 years), predominantly female (65%) and Caucasian (60%).

Table 12 lists the adverse reactions that occurred in ≥5% of XEOMIN-treated patients and greater than placebo.

Table 12: Adverse Reactions (≥5%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Blepharospasm Study 2 Adverse Reaction XEOMIN (N=74) % Placebo (N=34) % Eye disorders 38 21 Eyelid ptosis 19 9 Dry eye 16 12 Visual impairment including vision blurred 12 6 Gastrointestinal disorders 30 15 Dry mouth 16 3 Diarrhea 8 0 Infections and infestations 20 15 Nasopharyngitis 5 3 Respiratory tract infection 5 3 Nervous system disorders 14 9 Headache 7 3 General disorders and administration site conditions 11 9 Respiratory, thoracic and mediastinal disorders 11 3 Dyspnea 5 3 Upper Facial Lines [Glabellar Lines (GL), Horizontal Forehead Lines (HFL), and Lateral Canthal Lines (LCL)] In two placebo-controlled trials in 730 adult subjects with upper facial lines (GL, HFL, and LCL), 545 subjects received up to 64 Units of XEOMIN and 185 subjects received placebo.

XEOMIN-treated subjects were 19 to 76 years old and were predominantly female (82%).

Adverse reactions were reported for 62 of the 545 XEOMIN-treated subjects (11%) and for 14 of the 185 placebo-treated subjects (8%).

The most frequent adverse reactions ≥1% and greater for XEOMIN than placebo are presented in Table 13.

Table 13: Adverse Reactions (≥1%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Upper Facial Lines (GL, HFL, and LCL) Trials Upper Facial Lines (GL, HFL, and LCL) Adverse Reaction XEOMIN N=545 % Placebo N=185 % Injection site bruising 2 1 In the placebo-controlled trials, brow ptosis (0.7%) and injection site discomfort (0.6%) were also reported more frequently for XEOMIN than placebo-treated subjects.

In the two repeated dose upper facial lines (GL, HFL, and LCL) trials with up to three treatments of XEOMIN, adverse reactions were reported for 123 of the 720 subjects (17%).

Injection site hematoma was the most common adverse reaction, reported in 8% of subjects, followed by headache (3%), injection site bruising (3%) and brow ptosis (1%).

The incidence of these adverse reactions tended to decrease with subsequent treatments.

In both trials, all randomized subjects were followed up for 120 days before they could enter the open-label extension (OLEX) period which comprised two additional treatment cycles, with durations of 120 days each plus up to 30 days for eligibility reassessments per cycle.

During OLEX period, eligible subjects received simultaneous upper facial lines injections of XEOMIN at a total dose of 64 U in all three facial areas (20 U in GL, 20 U in HFL, and 24 U in LCL area).

Glabellar Lines In three placebo-controlled trials in 803 adult subjects with glabellar lines, 535 subjects received a single dose of 20 Units of XEOMIN and 268 subjects received placebo.

XEOMIN-treated subjects were 24 to 74 years old, and were predominantly female (88%).

The most frequent adverse reactions ≥1% and greater for XEOMIN than Placebo are presented in Table 14.

Table 14: Adverse Reactions (≥1%) and Greater for XEOMIN than Placebo: Double-Blind Phase of the Placebo-Controlled Glabellar Lines Trials Adverse Reaction XEOMIN N=535 % Placebo N=263 % Nervous system disorders Headache 5 2 In the placebo-controlled trials, facial paresis (0.7%), injection site hematoma (0.6%) and eyelid edema (0.4%) were also reported more frequently for XEOMIN than placebo-treated subjects.

In open-label, multiple-dose trials, adverse reactions were reported for 105 of the 800 subjects (13%).

Headache was the most common adverse reaction, reported in 7% of subjects, followed by injection site hematoma (1%).

Adverse reactions reported in less than 1% of subjects were: facial paresis (brow ptosis), muscle disorder (elevation of eyebrow), injection site pain, and eyelid edema.

6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of XEOMIN.

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: allergic dermatitis, dysarthria, dysphagia, eye swelling, eyelid edema, flu-like symptoms, herpes zoster, hypersensitivity, injection site pain, injection site reaction, localized allergic reactions (e.g., swelling, edema, erythema, pruritus or rash), muscle spasm, muscular weakness, myalgia, nausea, and persistent dry mouth (> 110 days).