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.

Chronic Sialorrhea in Adult Patients

The recommended total dose per treatment session is 100 Units. XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). The recommended total dose per treatment session is 100 Units. The dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 1).

Figure 1: Glands for Injection in Chronic Sialorrhea in Adult Patients

Use the following guidelines if locating salivary glands using anatomic landmarks:

• 1) To inject the parotid gland, find the midpoint on the line connecting the tragus and mandible angle (Site A and B, respectively, Figure 1), approximately at the height of the ear lobe. Deliver the injection one finger breadth anterior to this site (Star 1, Figure 1).
• 2) To inject the submandibular gland, find the midpoint between the angle of the mandible and the tip of the chin (Site B and C, respectively, Figure 1). Deliver the injection one finger breadth medial to the inferior surface of the mandible at this site (Star 2, Figure 1).

Table 1: Dosing by Gland for Treatment of Chronic Sialorrhea in Adult Patients

Gland(s)	Units Per Side	Total
Parotid gland(s)	30 Units	60 Units
Submandibular gland(s)	20 Units	40 Units
Both Glands	50 Units	100 Units

The concentration used in the clinical study after reconstitution was 5 Units/0.1mL. Determine the timing for repeat treatment based on the actual clinical need of the individual patient, and no sooner than every 16 weeks.

Chronic Sialorrhea in Pediatric Patients

XEOMIN is injected into the parotid and submandibular glands on both sides (i.e., 4 injection sites per treatment session). Ultrasound imaging is recommended to guide needle placement into the salivary glands. The body-weight adjusted dose is divided with a ratio of 3:2 between the parotid and submandibular glands (Table 2). XEOMIN has not been studied in children weighing less than 12 kg [see Clinical Studies (14.1)].

Figure 2: Glands for Injection in Chronic Sialorrhea in Pediatric Patients

Table 2: Dosing by Body Weight Class for Treatment of Chronic Sialorrhea in Pediatric Patients

Body weight	Parotid gland, each side		Submandibular gland, each side		Total dose, both glands, both sides
	Dose per gland	Volume per injection	Dose per gland	Volume per injection
12 kg or more to less than 15 kg	6 Units	0.24 mL	4 Units	0.16 mL	20 Units
15 kg or more to less than 19 kg	9 Units	0.36 mL	6 Units	0.24 mL	30 Units
19 kg or more to less than 23 kg	12 Units	0.48 mL	8 Units	0.32 mL	40 Units
23 kg or more to less than 27 kg	15 Units	0.6 mL	10 Units	0.4 mL	50 Units
27 kg or more to less than 30 kg	18 Units	0.72 mL	12 Units	0.48 mL	60 Units
30 kg or more	22.5 Units	0.9 mL	15 Units	0.6 mL	75 Units

The concentration used in the clinical study after reconstitution was 2.5 Units/0.1 mL. Determine the timing for repeat treatment based on the actual clinical need of the individual patient, and no sooner than every 16 weeks.

Upper Limb Spasticity in Adult Patients

Tailor the dosage, frequency, and number of injection sites to the individual patient based on the size, number, and location of muscles to be treated, severity of spasticity, presence of local muscle weakness, patient's response to previous treatment, and adverse event history with XEOMIN. Administer repeat XEOMIN treatments no sooner than every 12 weeks. In patients not previously treated with a botulinum toxin, begin initial dosing at the low end of the recommended dosing range and titrate as clinically necessary. Most patients in clinical studies were retreated between 12 and 14 weeks.

Table 3: XEOMIN Dosing by Muscle for Treatment of Adult Upper Limb Spasticity

Clinical Pattern Muscle	Units (Range)	Number of injection sites per muscle
Clenched Fist
Flexor digitorum superficialis	25 Units-100 Units	2
Flexor digitorum profundus	25 Units-100 Units	2
Flexed Wrist
Flexor carpi radialis	25 Units-100 Units	1-2
Flexor carpi ulnaris	20 Units-100 Units	1-2
Flexed Elbow
Brachioradialis	25 Units-100 Units	1-3
Biceps	50 Units-200 Units	1-4
Brachialis	25 Units-100 Units	1-2
Pronated Forearm
Pronator quadratus	10 Units-50 Units	1
Pronator teres	25 Units-75 Units	1-2
Thumb-in-Palm
Flexor pollicis longus	10 Units-50 Units	1
Adductor pollicis	5 Units-30 Units	1
Flexor pollicis brevis/Opponens pollicis	5 Units-30 Units	1

Figure 3: Muscles Involved In Adult Upper Limb Spasticity

Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy

Tailor the exact dosage, frequency, and number of injection sites to the individual patient based on size, number and localization of involved muscles; the severity of spasticity; and the presence of local muscle weakness.

The maximum recommended dose is 8 Units/kg, divided among affected muscles, up to a maximum dose of 200 Units per single upper limb. If both upper limbs are treated, do not exceed a total XEOMIN dosage of 16 Units/kg, up to a maximum of 400 Units.

Based on the selected dose, a reconstituted solution at a concentration between 1.25 Units/0.1 mL and 5 Units/0.1 mL is recommended [see Dosage and Administration (2.3)]. Determine the timing for repeat treatment based on the clinical need of the patient; administer repeat treatments no sooner than every 12 weeks. Most patients in clinical studies were retreated between 12 and 16 weeks.

Table 4 includes the recommended dose ranges for the treatment of the clinical patterns of flexed elbow, flexed wrist, pronated forearm, clenched fist, and thumb-in-palm.

Table 4: XEOMIN Dosing by Muscle for Treatment of Pediatric Upper Limb Spasticity, Excluding Spasticity Caused by Cerebral Palsy

Clinical Pattern   Muscle	Dosage		Number of Injection Sites per Muscle
	Range (Units/kg)	Maximum (Units)
Flexed Elbow
Brachioradialis	1-2	50	1-2
Biceps	2-3	75	1-3
Brachialis	1-2	50	1-2
Flexed Wrist
Flexor carpi radialis	1	25	1
Flexor carpi ulnaris	1	25	1
Pronated Forearm
Pronator quadratus	0.5	12.5	1
Pronator teres	1-2	50	1-2
Clenched Fist
Flexor digitorum superficialis	1	25	1
Flexor digitorum profundus	1	25	1
Thumb-in-Palm
Flexor pollicis longus	1	25	1
Adductor pollicis	0.5	12.5	1
Flexor pollicis brevis/ opponens pollicis	0.5	12.5	1

Figure 4: Muscles Injected for Pediatric Upper Limb Spasticity

Glabellar Lines

Equally distribute GL treatment to five equal intramuscular injections of 4 Units each. Inject 4 Units of reconstituted XEOMIN intramuscularly into each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a maximum recommended dose of 20 Units (see Figure 7).

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 corrugator injections at least 1 cm above the bony supraorbital ridge.

Horizontal Forehead Lines in Conjunction with Glabellar Lines

Treat HFL in conjunction with GL to minimize the potential for brow ptosis. The maximum recommended dose for treatment of HFL (20 Units) in conjunction with GL (20 Units) is 40 Units.

Equally distribute HFL treatment to 5 horizontally orientated intramuscular injection sites (4 Units each) into the frontalis muscle, at least 2 cm above the orbital rim (see Figure 7).

Lateral Canthal Lines

Inject 4 Units of reconstituted XEOMIN into 3 sites per side (6 total injection sites) in the lateral orbicularis oculi muscle for a total of 12 Units per side (24 Units overall). Place one injection in the horizontal extension of the lateral canthus approximately 1 cm lateral from the bony orbital rim. Place the other two injections approximately 1 cm above and below the area of the first injection (see Figure 7). Give injections with the needle bevel tip up and oriented away from the eye. Avoid injections too close to the zygomaticus major muscle to prevent lip ptosis.

Figure 7: Injection Sites for Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

Chronic Sialorrhea

Upper Limb Spasticity

Cervical Dystonia

Use a sterile needle (e.g., 26-gauge (0.45 mm diameter), 37 mm length for superficial muscles; or 22-gauge (0.70 mm diameter), 75 mm length for deeper musculature) in the intramuscular administration in the treatment of cervical dystonia.

Localization of the involved muscles with electromyographic guidance, ultrasound, or nerve stimulation techniques may be useful.

Blepharospasm

Use a sterile needle (e.g., 30-gauge (0.40 mm diameter), 12.5 mm length) in the intramuscular administration in the treatment of blepharospasm.

Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

Use a sterile needle [e.g., 30-33 gauge (0.3-0.2 mm diameter)], 13 mm length) for the intramuscular administration in the treatment of upper facial lines.

Chronic Sialorrhea

Upper Limb Spasticity

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 impairmentincluding 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).

Risk Summary

There are no adequate data on the developmental risk associated with the use of XEOMIN in pregnant women. XEOMIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. XEOMIN was embryotoxic in rats and increased abortions in rabbits when given at doses higher than the maximum recommended human dose (MRHD) for cervical dystonia (120 Units), on a body weight basis.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Risk Summary

There are no data on the presence of XEOMIN in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for XEOMIN and any potential adverse effects on the breastfed infant from XEOMIN or from the underlying maternal conditions.

Chronic Sialorrhea in Pediatric Patients

The safety and effectiveness of XEOMIN have been established by evidence from an adequate and well-controlled study of XEOMIN in patients 6 to 17 years of age with chronic sialorrhea [See Clinical Studies (14.1)]. Use of XEOMIN in patients 2 to 5 years of age is supported by the findings of efficacy and safety in patients 6 years and older with chronic sialorrhea, and by safety data in patients 2 to 5 years of age. Safety and effectiveness in pediatric patients below the age of 2 years have not been established [see Warnings and Precautions (5.1)].

Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy

Safety and effectiveness have been established in pediatric patients 2 to 17 years of age [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Studies (14.2)]. The safety and effectiveness of XEOMIN have been established by evidence from adequate and well-controlled studies of XEOMIN in patients 2 to 17 years of age with upper limb spasticity. A pediatric assessment for XEOMIN demonstrates that XEOMIN is safe and effective in another pediatric population. However, XEOMIN is not approved for such patient population due to marketing exclusivity for another botulinum toxin. Safety and effectiveness in pediatric patients below the age of 2 years have not been established [see Warnings and Precautions (5.1)].

Chronic Sialorrhea

Of the total number of 184 patients in the placebo-controlled study in chronic sialorrhea in adult patients [see Clinical Studies (14.1)], 107 were 65 years of age and over (46 treated with XEOMIN 100 Units, 44 treated with XEOMIN 75 Units, and 17 received placebo). No differences in safety or effectiveness were observed between older and younger patients. Other clinical studies have not identified differences in responses between older and younger patients, but increased sensitivity in older patients cannot be ruled out.

Upper Limb Spasticity

Of the total number of 283 patients in the placebo-controlled studies in upper limb spasticity in adult patients [see Clinical Studies (14.2)], 118 were 65 years of age and over (70 treated with XEOMIN and 48 received placebo), which included 12 patients 75 years of age and over (7 treated with XEOMIN and 5 received placebo). No overall differences in safety or effectiveness were observed between older and younger adult patients. Other clinical studies have not identified differences in responses between older and younger adult patients, but increased sensitivity in older patients cannot be ruled out.

Cervical Dystonia

Of the total number of 233 patients in the placebo-controlled study in cervical dystonia [see Clinical Studies (14.3)], 29 were 65 years of age and over (19 treated with XEOMIN and 10 received placebo). Of these, ten XEOMIN-treated patients and four placebo-treated patients experienced an adverse event. For patients 65 years of age and over treated with XEOMIN, the most common adverse events were dysphagia (21%) and asthenia (11%).

Blepharospasm

Of the total number of 169 patients in the placebo-controlled studies in blepharospasm [see Clinical Studies (14.4)], 61 were 65 years of age and over (45 treated with XEOMIN and 16 received placebo). No overall difference in effectiveness was observed between older and younger patients.

Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

Of the total number of 547 subjects in the placebo-controlled clinical studies for glabellar lines [see Clinical Studies (14.5)], 21 subjects were 65 years of age and over.

Of the total number of 730 subjects in the placebo-controlled clinical studies for upper facial lines GL, HFL, and LCL [see Clinical Studies (14.5)], 46 subjects were 65 years of age and over.

Clinical trials of XEOMIN showed no increase in the incidence of adverse events related to treatment with XEOMIN in patients 65 years of age and over but the trials did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Chronic Sialorrhea

Upper Limb Spasticity

Cervical Dystonia

Of the 227 patients treated with XEOMIN in the main phase and open-label extension period of the cervical dystonia clinical trial [see Clinical Studies (14.3)], 5 patients were positive for neutralizing antibodies at baseline, 1 (0.4%) patient (with unknown antibody status at baseline) was positive after treatment, and 4 (1.8%) additional patients developed neutralizing antibodies after treatment. All of these patients were pre-treated with onabotulinumtoxinA and/or abobotulinumtoxinA prior to enrollment in the study. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Blepharospasm

Of the 163 patients treated with XEOMIN in the main phase and open-label extension period of the blepharospasm clinical trials (Study 1 and Study 2) [see Clinical Studies (14.4)], 1 (0.6%) patient (with unknown antibody status at baseline) was positive for neutralizing antibodies after treatment. The patient had not received a botulinum toxin treatment in the 12 months prior to enrollment in the studies. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Glabellar Lines

Of the 464 patients treated with XEOMIN in the main phase and open-label extension period of the glabellar lines clinical trials (GL-1 and GL-2) [see Clinical Studies (14.5)], no patients developed neutralizing antibodies after treatment. No patients demonstrated a secondary lack of treatment response due to neutralizing antibodies.

Carcinogenesis

Studies to evaluate the carcinogenic potential of XEOMIN have not been conducted.

Mutagenesis

Genotoxicity studies have not been conducted for XEOMIN.

Impairment of Fertility

In a fertility and early embryonic development study in rabbits, males and females were dosed with XEOMIN (1.25 Units/kg, 2.5 Units/kg, or 3.5 Units/kg) intramuscularly every two weeks for 5 and 3 doses, respectively, beginning 2 weeks prior to mating. No effects on mating or fertility were observed. The highest dose tested is approximately twice the maximum recommended human dose for cervical dystonia (120 Units) on a body weight basis.

Chronic Sialorrhea in Adult Patients

The efficacy and safety of XEOMIN for the treatment of chronic sialorrhea in adult patients were evaluated in a double-blind, placebo-controlled clinical trial (NCT02091739) that enrolled a total of 184 patients with chronic sialorrhea resulting from Parkinson's disease, atypical parkinsonism, stroke, or traumatic brain injury, that was present for at least three months. Patients with a history of aspiration pneumonia, amyotrophic lateral sclerosis, salivary gland or duct malformation, and gastroesophageal reflux disease were excluded. The study consisted of a 16-week main phase, followed by an extension period of dose-blinded treatment with XEOMIN.

In the main phase, a fixed total dose of XEOMIN (100 Units or 75 Units) or placebo was administered into the parotid and submandibular salivary glands in a 3:2 dose ratio. The co-primary efficacy variables were the change in unstimulated Salivary Flow Rate (uSFR, Table 15) and the change in Global Impression of Change Scale (GICS, Table 16) at Week 4 post-injection. A total of 173 treated patients completed the main phase of the study. For both the uSFR and GICS, XEOMIN 100 Units was significantly better than placebo (see Table 15 and Table 16). XEOMIN 75 Units was not significantly better than placebo.

Table 15: Mean Change in uSFR (g/min) from Baseline at Week 4, 8, 12, and 16 of Main Phase

	XEOMIN 100 Units	Placebo
	N=73	N=36
Week 4p=0.004	-0.13	-0.04
Week 8	-0.13	-0.02
Week 12	-0.12	-0.03
Week 16	-0.11	-0.01

Table 16: Mean GICS at Week 4, 8, 12, and 16 of Main Phase

	XEOMIN 100 Units	Placebo
	N=74	N=36
Week 4p=0.002	1.25	0.67
Week 8	1.30	0.47
Week 12	1.21	0.56
Week 16	0.93	0.41

In the extension period, patients received up to three additional treatments with XEOMIN 100 Units or 75 Units every 16±2 weeks, for a total exposure duration of up to 64 weeks. Patients had periodic dental examinations to monitor for changes in dentition and oral mucosa. A total of 151 patients completed the extension period.

Chronic Sialorrhea in Pediatric Patients

The efficacy and safety of XEOMIN for the treatment of chronic sialorrhea in pediatric patients were evaluated in a prospective, randomized, double-blind, placebo-controlled (ages 6-17 years), parallel-group, multicenter trial (NCT02270736) that enrolled and treated a total of 216 pediatric patients 6-17 years of age with chronic sialorrhea associated with cerebral palsy, other genetic or congenital disorders, or traumatic brain injury. An additional 35 patients 2-5 years of age were treated with open-label XEOMIN in that study. The study consisted of a 16-week main phase, followed by an open-label extension period of treatment with XEOMIN where patients could receive up to 3 additional treatments with XEOMIN every 16 ± 2 weeks, for a total exposure duration of up to 64 weeks (222 patients completed the extension period).

In the main phase, patients 6-17 years of age were administered a total dose of XEOMIN according to body weight (up to 75 Units), or placebo, into the parotid and submandibular glands in a 3:2 dose ratio, using ultrasound guidance. Patients 2-5 years of age all received open-label treatment with XEOMIN, according to body weight, using ultrasound guidance. Patients with a body weight <12 kg were excluded.

The primary efficacy analysis was conducted in the 6-17 years of age patient group. The co-primary endpoints were the change in unstimulated Salivary Flow Rate (uSFR, Table 17) and carer's Global Impression of Change Scale (GICS, Table 18) at Week 4 post-injection.

For both the uSFR and GICS, XEOMIN was statistically significantly better than placebo (see Table 17 and Table 18).

Table 17: Mean change in uSFR (g/min) from Baseline at Week 4, 8, 12, and 16 of Main Phase

	XEOMIN (6-17 years) N = 148	Placebo (6-17 years) N=72
Week 4p=0.0012	-0.14	-0.07
Week 8	-0.16	-0.07
Week 12	-0.16	-0.06
Week 16	-0.15	-0.08

Table 18: Mean carer's GICS at Week 4, 8, 12, and 16 of Main Phase

	XEOMIN (6-17 years) N = 148	Placebo (6-17 years) N=72
Week 4p=0.0320	0.91	0.63
Week 8	0.94	0.54
Week 12	0.87	0.47
Week 16	0.77	0.38

Efficacy in pediatric patients 2 to 5 years of age is extrapolated from the finding of efficacy in older pediatric patients.

Upper Limb Spasticity in Adult Patients

The efficacy and safety of XEOMIN for the treatment of upper limb spasticity in adult patients were evaluated in two Phase 3, randomized, multi-center, double-blind studies.

Study 1 (NCT01392300) and Study 2 (NCT00432666) were both prospective, double-blind, placebo-controlled, randomized, multi-center trials with an open-label extension period (OLEX) to investigate the efficacy and safety of XEOMIN in the treatment of post-stroke spasticity of the upper limb. For patients who had previously received botulinum toxin treatment in any body region, Study 1 and Study 2 required that ≥12 months and ≥4 months, respectively, had passed since the most recent botulinum toxin administration.

Study 1 consisted of a 12-week main phase followed by three 12-week OLEX treatment cycles for a total exposure duration of 48 weeks. The study included 317 treatment-naïve patients who were at least three months post-stroke in the main study period (210 XEOMIN and 107 placebo). During the main period, XEOMIN (fixed total dose of 400 Units) and placebo were administered intramuscularly to the defined primary target clinical pattern chosen from among the flexed elbow, flexed wrist, or clenched fist patterns and to other affected muscle groups. 296 treated patients completed the main phase and participated in the first OLEX cycle. Each OLEX cycle consisted of a single treatment session (XEOMIN 400 Units total dose, distributed among all affected muscles) followed by a 12-week observation period.

Study 2 consisted of a 12-to-20-week main phase followed by an OLEX period of 48 – 69 weeks, for up to 89 weeks of exposure to XEOMIN. The study included 148 treatment-naïve and pre-treated patients with a confirmed diagnosis of post-stroke spasticity of the upper limb who were at least six months post-stroke (73 XEOMIN and 75 placebo). During the main period, for each patient, the clinical patterns of flexed wrist and clenched fist were treated with fixed doses (90 Units and 80 Units, respectively). Additionally, if other upper limb spasticity patterns were present, the elbow, forearm and thumb muscles could be treated with fixed doses of XEOMIN per muscle. 145 patients completed the main phase and participated in the OLEX period, during which time the dosing of each involved muscle could be adapted individually. During the main and OLEX periods, the maximum total dose per treatment session and 12-week interval was 400 Units.

The average XEOMIN doses injected into specific muscles and the number of injection sites per muscle in Study 1 and Study 2 are presented in Table 19.

Table 19: Doses Administered to Individual Muscles (Main Period) in Adult Upper Limb Spasticity Study 1 and Study 2 Intent to Treat (ITT)

Muscle Group	Muscle	Study 1 Units Injected	Injection Site Per Muscle	Study 2 Units Injected	Injection Site Per Muscle
		XEOMIN (N=210) Mean±SD	XEOMIN Median (Min; Max)	XEOMIN (N=73) Mean±SD	XEOMIN Median (Min; Max)
All	Overall	400 ± 2 Units	--	307 ± 77 Units	--
Elbow flexors	Overall	151 ± 50 Units	5 (1; 11)	142 ± 30 Units	5 (2; 9)
	Biceps	90 ± 21 Units	3 (1; 4)	80 ± 0 Units	3 (2; 4)
	Brachialis	52 ± 26 Units	2 (1; 4)	50 ± 0 Units	2 (1; 2)
	Brachioradialis	43 ± 16 Units	2 (1; 3)	60 ± 2Units	2 (1; 3)
Wrist flexors	Overall	112 ± 43 Units	4 (1; 6)	90 ± 0 Units	4 (4; 4)
	Flexor carpi radialis	58 ± 22 Units	2 (1; 3)	50 ± 0 Units	2 (2; 2)
	Flexor carpi ulnaris	56 ± 22 Units	2 (1; 3)	40 ± 0 Units	2 (2; 2)
Finger flexors	Overall	104 ± 35 Units	4 (1; 4)	80 ± 0 Units	4 (4; 4)
	Flexor digitorum profundus	54 ± 19 Units	2 (1; 2)	40 ± 0 Units	2 (2; 2)
	Flexor digitorum superficialis	54 ± 19 Units	2 (1; 2)	40 ± 0 Units	2 (2; 2)
Forearm pronators	Overall	52 ± 24 Units	2 (1; 3)	47 ± 16 Units	2 (1; 3)
	Pronator quadratus	26 ± 13 Units	1 (1; 1)	25 ± 0 Units	1 (1; 1)
	Pronator teres	42 ± 13 Units	1 (1; 2)	40 ± 0 Units	1.5 (1; 2)
Thumb flexors/ adductors	Overall	37 ± 25 Units	2 (1; 4)	25 ± 10 Units	1.5 (1; 3)
	Adductor pollicis	14 ± 8 Units	1 (1; 1)	10 ± 0 Units	1 (1; 1)
	Flexor pollicis brevis / opponens pollicis	14 ± 9 Units	1 (1; 1)	10 ± 0 Units	1 (1; 1)
	Flexor pollicis longus	26 ± 16 Units	1 (1; 2)	20 ± 0 Units	1 (1; 1)

In Study 1, the primary efficacy variable was the change from baseline in Ashworth Scale (AS) score of the primary target clinical pattern determined by the investigator at the Week 4 visit. The Ashworth Scale is a clinical measure of the severity of spasticity by judging resistance to passive movement. The spasticity of the elbow flexors, wrist flexors, finger flexors, and thumb muscles as well as the forearm pronators was assessed on the 0 to 4-point Ashworth scale at each visit. The co-primary efficacy variable of Study 1 was the Investigator's Global Impression of Change Scales (GICS) after 4 Weeks of treatment with XEOMIN or placebo. The GICS is a global measure of a subject's functional improvement. Investigators were asked to evaluate the subject's global change in spasticity of the upper limb due to treatment, compared to the condition before the last injection. The response was assessed using a 7-point Likert scale that ranges from –3 (very much worse) to +3 (very much improved). XEOMIN was considered to be superior to placebo in Study 1 only if statistical significance was reached in both the AS and GICS variables.

The primary efficacy results are displayed in Table 20.

Table 20: Efficacy Results by Patterns of Spasticity in Adult Upper Limb Spasticity Study 1, Week 4

	Mean Change in Ashworth Scale
	XEOMIN (N=171)	Placebo (N=88)
The analysis is based on Last Observation Carried Forward in the Intent To Treat population. p<0.001
Total Primary Target Clinical Pattern (flexed wrist, flexed elbow, and clenched fist)	-0.9	-0.5

A greater percentage of XEOMIN-treated subjects (43%) than placebo-treated subjects (23%) reported 'very much improved' and 'much improved' in their spasticity (see Figure 8).

Figure 8: Investigator's GICS in Adult Upper Limb Spasticity Study 1

Upper Limb Spasticity in Pediatric Patients

Study 1 (NCT02002884) was a prospective, double-blind, dose-response, randomized, multi-center trial with an open-label extension period to evaluate the efficacy and safety of XEOMIN for the treatment of upper limb spasticity in pediatric patients. Study 1 enrolled a total of 350 pediatric patients 2 to 17 years of age with upper limb spasticity in one or both upper limbs. In the double-blind main period of Study 1, patients were randomized to one of three dosages of XEOMIN: 2 Units/kg (maximum 50 Units per upper limb), 6 Units/kg (maximum 150 Units per upper limb); or 8 Units/kg (maximum 200 Units per upper limb). The maximum dose, if both upper limbs were treated, respectively was 4 Units/kg (maximum 100 Units), 12 Units/kg (maximum 300 Units), or 16 Units/kg (maximum 400 Units). For treatment of flexed elbow, injection of biceps brachii was mandatory. The investigator could select 1 of the 2 other muscles contributing to spasticity of elbow flexion (i.e., brachialis and brachioradialis) for injection. For patients needing treatment for a flexed wrist, both the flexor carpi radialis and flexor carpi ulnaris were injected. Study 1 used a dose-response design, in which the two highest dosages of XEOMIN (8 Units/kg and 6 Units/kg) were compared to the lowest dosage (2 Units/kg), which served as control. In the absence of a placebo control, the efficacy of the 2 Units/kg dosage of XEOMIN could not be evaluated in Study 1.

The co-primary efficacy variables in Study 1 were the change from baseline on the Ashworth Scale for the primary clinical target pattern (i.e., elbow flexors or wrist flexors), and the Investigator's Global Impression of Change Scale (GICS), both at Week 4. The GICS is a global measure of a subject's functional improvement based on a 7-point Likert scale that ranges from -3 = very much worse to +3 = very much improved.

As displayed in Table 21, the change from baseline in Ashworth Scale score was significantly greater for patients treated with XEOMIN 8 Units/kg than for patients treated with XEOMIN 2 Units/kg. The difference in GICS score between patients treated with XEOMIN 8 Units/kg and those treated with XEOMIN 2 Units/kg did not reach statistical significance. However, the clinical meaningfulness of the difference in Ashworth Scale score change between patients treated with XEOMIN 8 Units/kg and those treated with XEOMIN 2 Units/kg was established by a responder analysis, in which the proportion of patients with a 1-point change or greater on the Ashworth Scale was examined. In that analysis, 86% of patients treated with XEOMIN 8 Units/kg met the responder definition, compared to 71% of patients treated with XEOMIN 2 Units/kg (nominal p value = 0.0099).

There was no significant difference in change from baseline in Ashworth Scale score, GICS score, or proportion of responders between patients treated with XEOMIN 6 Units/kg and those treated with XEOMIN 2 Units/kg. Therefore, the efficacy of a 6 Units/kg dosage of XEOMIN for the treatment of upper limb spasticity in pediatric patients was not established in Study 1.

Table 21: Ashworth Scale and GICS Efficacy Results in Pediatric Upper Limb Spasticity Study 1, Week 4

	XEOMIN 2 Units/kg (N=87)	XEOMIN 8 Units/kg (N=176)
LS = Least Square Mean difference CI = Confidence Interval
Ashworth Scale
Mean Change from Baseline at Week 4	-0.9	-1.2
LS Mean Difference versus XEOMIN 2 Units/kg (95% CIs)	--	-0.22p-value versus low dose group <0.05 (-0.40, -0.04)
GICS
Mean at Week 4	1.6	1.7
LS Mean Difference versus XEOMIN 2 Units/kg (95% CIs)	--	0.09 (-0.10, 0.28)

Treatment-Naïve Patients

The efficacy and safety of XEOMIN for the treatment of blepharospasm in treatment-naïve patients were evaluated in Study 1 (NCT01896895), a randomized, double-blind, placebo-controlled, multi-center trial in a total of 61 patients. Patients had a clinical diagnosis of blepharospasm, with a baseline Jankovic Rating Scale (JRS) severity subscore ≥2. Patients were defined as treatment-naïve if at least 12 months had passed since their last botulinum toxin treatment for blepharospasm. During the placebo-controlled phase, a fixed total dose of 25 Units XEOMIN (n=22), 50 Units XEOMIN (n=19), or placebo (n=20) was administered intramuscularly at 6 injection sites per eye (Figure 9). Of the 61 patients randomized, 55 patients completed the placebo-controlled phase. Patients only continued to the open-label extension (OLEX) period if they had a confirmed need for a re-injection by week 20 of the placebo-controlled phase. A total of 39 patients entered and completed the OLEX phase.

The primary efficacy variable was the change from baseline in JRS Severity subscore determined at Week 6 after the injection. The 50 Unit treatment group demonstrated statistically significant improvements compared to placebo, with a difference of -1.2 (p=0.0004). The change from baseline in the JRS Severity subscore for the 25 Unit treatment group 6 weeks after the injection was not statistically significant, with a difference of -0.5 (p=0.1452) compared to placebo (see Figure 9).

Figure 9: Frequency Distribution of Changes from Baseline JRS Severity Subscore at Week 6 for Treatment-Naïve Patients

Pre-Treated Patients

The efficacy and safety of XEOMIN for the treatment of blepharospasm patients pre-treated with onabotulinumtoxinA (Botox) were evaluated in Study 2 (NCT00406367), a randomized, double-blind, placebo-controlled, multi-center trial in a total of 109 patients. Patients had a clinical diagnosis of benign essential blepharospasm, with baseline JRS Severity subscore ≥2, and a stable satisfactory therapeutic response to previous administrations of onabotulinumtoxinA (Botox). At least 10 weeks had to have elapsed since the most recent onabotulinumtoxinA administration. Patients with any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (2:1) to receive a single administration of XEOMIN (n=75) or placebo (n=34). Each patient in the XEOMIN group received a XEOMIN treatment (dose, volume, dilution, and injection sites per muscle) that was similar to the most recent onabotulinumtoxinA injection sessions prior to study entry. The highest dose permitted in this study was 100 Units (50 Units per eye); the mean XEOMIN dose was 33 Units per eye.

In Table 24 the most frequently injected sites, the median dose per injection site, and the median number (and range) of injection sites per eye are presented.

Table 24: Median Dose and Median Number of Injection Sites per Eye (Blepharospasm)

Injection Area	Median Units XEOMIN	Median Number of Injection Sites (Min-Max)
Temporal Area	13	2 (1 – 6)
Eyebrow Area	5	1 (1 – 4)
Upper Lid Area	10	2 (1 – 4)
Lower Lid Area	8	2 (1 – 3)
Orbital Rim	5	1 (1 – 3)

Patients were assessed during clinic visits at Weeks 3 and 6, and then by telephone or at clinic visits every two weeks up to Week 20.

The mean age of the study patients was 62 years, 65% of the patients were women, and 83% were White. The study was completed by 94% of study patients. Approximately one third of patients had other dystonic phenomena; in all but 1% this was limited to facial, cervical, perioral and mandibular muscles. No patients discontinued the study prematurely due to adverse events.

The primary efficacy endpoint was the change in the JRS Severity subscore from baseline to Week 6 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's most recent value (i.e., last observation carried forward). In the ITT population, the difference between the XEOMIN group and the placebo group in the change of the JRS Severity subscore from baseline to Week 6 was -1.0 (95% CI -1.4; -0.5) points. Comparison of the XEOMIN group to the placebo group was statistically significant at p<0.001.

Figure 10: Frequency Distribution of Changes from Baseline JRS Severity Subscore at Week 6

Examination of age and gender subgroups did not identify substantial differences in response to XEOMIN among these subgroups.

Glabellar Lines

Two identically designed randomized, double-blind, multi-center, placebo controlled clinical trials (Studies GL-1 and GL-2) were conducted to evaluate XEOMIN for use in the temporary improvement of moderate to severe glabellar lines. The trials enrolled 547 healthy adult patients with glabellar lines of at least moderate severity at maximum frown. Three hundred sixty six (366) subjects were treated with 20 Units of XEOMIN and 181 subjects received placebo. Subjects were excluded if they had marked ptosis, deep dermal scarring, or an inability to lessen glabellar lines, even by physically spreading them apart. The mean age of trial subjects was 46 years. The majority of subjects were female (86% and 93% in Studies GL-1 and GL-2, respectively), and predominantly White (89% and 65% respectively). The trial subjects received either 20 Units of XEOMIN or an equal amount of placebo. The total dose was delivered in 5 equally divided intramuscular injections of 4 Units each to specific sites (see Figure 7). Subjects were followed up for 120 days.

Investigators and subjects assessed efficacy at maximum frown on Day 30 of treatment using a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Composite treatment success was defined as a 2-grade improvement on this scale compared to baseline for both the investigator's and subject's assessments on Day 30. The percentage of subjects with treatment success was greater on the XEOMIN arm than the placebo arm at Day 30 in both trials (see Table 26).

Table 26: Treatment Success at Day 30 (at Least 2 Grades Improvement from Baseline at Maximum Frown) in Adults with GL in Studies GL-1 and GL-2

	GL-1		GL-2
	XEOMIN (N=184)	Placebo (N=92)	XEOMIN (N=182)	Placebo (N=89)
Composite Treatment SuccessSuccess on both the Investigator and Subject Assessments	111 (60%)	0 (0%)	87 (48%)	0 (0%)
Investigator Assessment	141 (77%)	0 (0%)	129 (71%)	0 (0%)
Subject Assessment	120 (65%)	0 (0%)	101 (55%)	1 (1%)

Upper Limb Spasticity and Cervical Dystonia

Package	XEOMIN 50 Units	XEOMIN 100 Units	XEOMIN 200 Units
Carton with one single-dose vial	NDC 0259-1605-01	NDC 0259-1610-01	NDC 0259-1620-01

Chronic Sialorrhea and Blepharospasm

Package	XEOMIN 50 Units	XEOMIN 100 Units
Carton with one single-dose vial	NDC 0259-1605-01	NDC 0259-1610-01

Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

Package	XEOMIN 50 Units	XEOMIN 100 Units
Carton with one single-dose vial	NDC 46783-161-01	NDC 46783-160-01