Incobotulinumtoxina

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.

2 DOSAGE AND ADMINISTRATION Chronic Sialorrhea : Chronic Sialorrhea in Adults: the recommended total dose is 100 Units per treatment session consisting of 30 Units per parotid gland and 20 Units per submandibular gland, no sooner than every 16 weeks ( 2.2 ) Chronic Sialorrhea in Pediatric Patients: the recommended dose is based on body weight administered in a 3:2 dose ratio into the parotid and submandibular glands, respectively, no sooner than every 16 weeks; ultrasound guidance recommended ( 2.2 ) Upper limb spasticity, cervical dystonia, and blepharospasm: the optimum dose, frequency, and number of injection sites in the treated muscle(s) should be based on severity and prior treatment response in patients previously treated with botulinum toxin; individualize dosing for each patient: Upper Limb Spasticity in Adults: the recommended total dose is up to 400 Units, divided among affected muscles ( 2.3 ) Upper Limb Spasticity in Pediatric Patients, excluding spasticity caused by cerebral palsy: the recommended total dose is 8 Units/kg (maximum 200 Units) per single upper limb or 16 Units/kg (maximum 400 U) in both upper limbs, divided among affected muscles ( 2.3 ) Cervical Dystonia: the recommended initial dose is 120 Units per treatment session ( 2.4 ) Blepharospasm: the recommended initial dose is 50 Units (25 Units per eye) ( 2.5 ) Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines): When treating all three areas simultaneously (glabellar lines, horizontal forehead lines, and lateral canthal lines), the maximum recommended dose is 64 Units ( 2.6 ). When not treating simultaneously: Glabellar Lines: four Units into each of five sites, for a maximum dose of 20 Units Horizontal Forehead Lines treated simultaneously with Glabellar Lines: for HFL four Units into each of five sites (20 Units) and four Units into each of five GL sites (20 Units), for a maximum dose of 40 Units Lateral Canthal Lines: four Units into each of three sites per side (six injection sites in total), for a maximum dose of 12 Units per side (24 Units in total) Administer retreatment with XEOMIN no more frequently than every three months. Reconstituted XEOMIN: Is intended for intramuscular or intraglandular injection in the parotid and submandibular glands only ( 2.7 ) Use for only one injection session and for only one patient ( 2.7 ) Instructions are specific for 50 Unit, 100 Unit, and 200 Unit vials ( 2.7 ) Store in a refrigerator (2°C to 8°C) and use within 24 hours ( 2.7 ) 2.1 Instructions for Safe Use The potency Units of XEOMIN for injection are specific to the preparation and assay method utilized. Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions (5.2) and Description (11) ] . Reconstituted XEOMIN is intended for intramuscular or intra-salivary gland injection only. Do not exceed the recommended maximum cumulative dose in a treatment session for any indication. 2.2 Recommended Dose for Chronic Sialorrhea 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. Figure 1 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. Figure 2 2.3 Recommended Dose for Upper Limb Spasticity 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 Figure 3 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 Figure 4 2.4 Recommended Dose for Cervical Dystonia The recommended initial dose of XEOMIN for cervical dystonia is 120 Units. In previously treated patients, their past dose, response to treatment, duration of effect, and adverse event history should be taken into consideration when determining the XEOMIN dose. In the treatment of cervical dystonia, XEOMIN is usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, and/or the trapezius muscle(s) (see Figure 5 ). This list is not exhaustive, as any of the muscles responsible for controlling head position may require treatment [see Clinical Studies (14.3) ]. The dose and number of injection sites in each treated muscle should be individualized based on the number and location of the muscle(s) to be treated, the degree of spasticity/dystonia, muscle mass, body weight, and response to any previous botulinum toxin injections. The frequency of XEOMIN repeat treatments should be determined by clinical response, but should generally be no more frequent than every 12 weeks [see Clinical Studies (14.3) ]. Figure 5: Muscles Involved in Cervical Dystonia Figure 5 2.5 Recommended Dose for Blepharospasm In treatment-naïve patients, the recommended initial dose of XEOMIN is 50 Units (25 Units per eye). In patients previously treated with a botulinum toxin A, consider their past dose, response to treatment, duration of effect, and adverse event history when determining the XEOMIN dose. Do not exceed a total XEOMIN dose of 100 Units per treatment session (50 Units per eye). Inject XEOMIN into the lateral and medial orbicularis oculi muscle of the upper lid; lateral canthus and the lateral orbicularis oculi muscle of the lower lid; and the corrugator muscle, if necessary (see Figure 6 ). The number and location of injections may be changed in response to adverse reactions or based on the patient's response to treatment, but do not exceed a total dose of 50 Units per eye. Figure 6: Injection Sites for Blepharospasm Determine the frequency of XEOMIN repeat treatments by clinical response but administer repeat treatments no more frequent than every 12 weeks [see Clinical Studies (14.4) ] . Figure 6 2.6 Recommended Dose for Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines) The maximum recommended dose of XEOMIN for simultaneous treatment of upper facial lines [i.e., glabellar lines (GL), horizontal forehead lines (HFL) and lateral canthal lines (LCL)] in adult patients is 64 Units, comprised of 20 Units for GL, 20 Units for HFL, and 24 Units for LCL. Administer retreatment with XEOMIN no more frequently than every three months. When not treating upper facial lines (GL, HFL, and LCL) simultaneously in adult patients, refer to the following instructions: 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) Figure 7 2.7 Preparation and Reconstitution Technique Prior to injection, reconstitute each vial of XEOMIN with sterile, preservative-free 0.9% Sodium Chloride Injection, USP [see Dosage Form and Strengths (3) ] . A 20-27 gauge short bevel needle is recommended for reconstitution. Draw up an appropriate amount of preservative-free 0.9% Sodium Chloride Injection, USP into a syringe (see Table 5 ). Clean the exposed portion of the rubber stopper of the vial with alcohol (70%) prior to insertion of the needle. After vertical insertion of the needle through the rubber stopper, the vacuum will draw the saline into the vial. Gently inject any remaining saline into the vial to avoid foam formation. If the vacuum does not pull the saline into the vial, then XEOMIN must be discarded. Remove the syringe from the vial and mix XEOMIN with the saline by carefully swirling and inverting/flipping the vial – do not shake vigorously. Reconstituted XEOMIN is a clear, colorless solution free of particulate matter. Do not use XEOMIN if the reconstituted solution has a cloudy appearance or contains floccular or particulate matter. After reconstitution, use XEOMIN for only one injection session and for only one patient. Administer reconstituted XEOMIN within 24 hours after dilution. During this time period, store unused reconstituted XEOMIN in the original container in a refrigerator 2°C -8°C (36°F -46°F) for up to 24 hours until time of use. XEOMIN vials are for single-dose only. Discard any unused portion. Diluent volumes for reconstitution of XEOMIN are indicated in Table 5. Table 5: Diluent Volumes for Reconstitution of XEOMIN Volume of preservative-free 0.9% Sodium Chloride Injection, USP 50 Unit Vial: Resulting dose in Units per 0.1 mL 100 Unit Vial: Resulting dose in Units per 0.1 mL 200 Unit Vial: Resulting dose in Units per 0.1 mL 0.25 mL 20 Units - - 0.5 mL 10 Units 20 Units 40 Units 1 mL 5 Units 10 Units 20 Units 1.25 mL 4 Units 8 Units 16 Units 2 mL 2.5 Units 5 Units 10 Units 2.5 mL 2 Units 4 Units 8 Units 4 mL 1.25 Units 2.5 Units 5 Units 5 mL 1 Unit 2 Units 4 Units 8 mL When using 8 mL of diluent for a 100 Unit or 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 100 Unit or 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 8 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently. - 1.25 Units 2.5 Units 16 mL When using 16 mL of diluent for a 200 Unit vial of XEOMIN, complete the following steps: Reconstitute a 200 Unit vial of XEOMIN with 4 mL of preservative-free 0.9% Sodium Chloride Injection, USP, following instructions above. Withdraw 12 mL of preservative-free 0.9% Sodium Chloride Injection, USP, into an appropriately sized syringe for 16 mL in total. Using the same syringe, draw up the 4 mL of XEOMIN solution from the reconstituted vial and mix gently. - - 1.25 Units 2.8 Administration Reconstituted XEOMIN is intended for intramuscular or intra-salivary gland injection only. If proposed injection sites are marked with a pen, DO NOT inject XEOMIN through the pen marks; otherwise a permanent tattooing effect may occur. For intramuscular injections, the number of injection sites is dependent upon the size of the muscle to be treated and the volume of reconstituted XEOMIN injected. Inject XEOMIN carefully when injected at sites close to sensitive structures, such as the carotid artery, lung apices, and esophagus. Before administering XEOMIN, the healthcare provider should be familiar with the patient's anatomy and any anatomic alterations, e.g., due to prior surgical procedures. Chronic Sialorrhea Chronic Sialorrhea in Adult Patients Use a sterile needle (e.g., 27-30 gauge (0.30-0.40 mm diameter), 12.5 mm length) for intra-salivary gland administration for the treatment of chronic sialorrhea. Inject XEOMIN close to the center of the gland. The salivary glands can be located using ultrasound imaging or surface anatomical landmarks [see Dosage and Administration (2.3) ]. Chronic Sialorrhea in Pediatric Patients Use a sterile needle (e.g., 27-30 gauge (0.30-0.40 mm diameter), 12.5 mm length) for intra-salivary gland administration for the treatment of chronic sialorrhea. Inject XEOMIN close to the center of the gland. Ultrasound guidance is recommended for the localization of the involved salivary glands [see Clinical Studies (14.2) ] . Upper Limb Spasticity Upper Limb Spasticity in Adult Patients 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 upper limb spasticity in adults. Localization of the involved muscles with electromyographic guidance, nerve stimulation, or ultrasound techniques is recommended. Upper Limb Spasticity in Pediatric Patients, Excluding Spasticity Caused by Cerebral Palsy Use a sterile needle (e.g., 30-gauge (0.30 mm diameter), 25 mm length for superficial muscles; or 27-gauge (0.40 mm diameter), 37 mm length for deeper musculature) in the intramuscular administration in the treatment of upper limb spasticity in pediatric patients. Localization of the involved muscles with techniques such as electromyographic guidance, nerve stimulation, or ultrasound is recommended. 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. 2.9 Monitoring to Assess Effectiveness The median onset of XEOMIN treatment effect occurs within two to seven days after injection. The typical duration of effect of each treatment is up to 12-16 weeks; however, the duration of effect may vary in individual patients.

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).

12.3 Pharmacokinetics Using currently available analytical technology, it is not possible to detect XEOMIN in the peripheral blood following intramuscular or intraglandular injection at the recommended doses.