BOTOX

OnabotulinumtoxinA is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A, and intended for intramuscular, intradetrusor and intradermal use. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying. The primary release procedure for BOTOX uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to AbbVie’s products BOTOX and BOTOX Cosmetic. One Unit of BOTOX corresponds to the calculated median intraperitoneal lethal dose (LD 50 ) in mice. Due to specific details of this assay such as the vehicle, dilution scheme, and laboratory protocols, Units of biological activity of BOTOX cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. The specific activity of BOTOX is approximately 20 Units/nanogram of neurotoxin protein complex. Each vial of BOTOX (onabotulinumtoxinA) for injection contains either 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.

BOTOX is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for: Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication ( 1.1 ) Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication ( 1.1 ) Treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. ( 1.2 ) Prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer) ( 1.3 ) Treatment of spasticity in patients 2 years of age and older ( 1.4 ) Treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain ( 1.5 ) Treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients ( 1.6 ) Treatment of blepharospasm associated with dystonia in patients 12 years of age and older ( 1.7 ) Treatment of strabismus in patients 12 years of age and older ( 1.7 ) Limitations of Use Safety and effectiveness of BOTOX have not been established for: Prophylaxis of episodic migraine (14 headache days or fewer per month) ( 1.3 ) Treatment of hyperhidrosis in body areas other than axillary ( 1.6 ) 1.1 Adult Bladder Dysfunction Overactive Bladder BOTOX for injection is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication. Detrusor Overactivity associated with a Neurologic Condition BOTOX is indicated for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., SCI, MS) in adults who have an inadequate response to or are intolerant of an anticholinergic medication. 1.2 Pediatric Detrusor Overactivity A ssociated with a Neurologic Condition BOTOX is indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. 1. 3 Chronic Migraine BOTOX is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer). Limitations of Use Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in seven placebo-controlled studies. 1. 4 Spasticity BOTOX is indicated for the treatment of spasticity in patients 2 years of age and older. Limitations of Use BOTOX has not been shown to improve upper extremity functional abilities, or range of motion at a joint affected by a fixed contracture. 1. 5 Cervical Dystonia BOTOX is indicated for the treatment of adults with cervical dystonia, to reduce the severity of abnormal head position and neck pain associated with cervical dystonia. 1. 6 Primary Axillary Hyperhidrosis BOTOX is indicated for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents. Limitations of Use The safety and effectiveness of BOTOX for hyperhidrosis in other body areas have not been established. Weakness of hand muscles and blepharoptosis may occur in patients who receive BOTOX for palmar hyperhidrosis and facial hyperhidrosis, respectively. Patients should be evaluated for potential causes of secondary hyperhidrosis (e.g., hyperthyroidism) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease. Safety and effectiveness of BOTOX have not been established for the treatment of axillary hyperhidrosis in pediatric patients under age 18. 1 . 7 Blepharospasm and Strabismus BOTOX is indicated for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and older.

Follow indication-specific dosage and administration recommendations. In a 3 month interval, do not exceed a total dose of: • Adults: 400 Units • Pediatrics: the lesser of 10 Units/kg or 340 Units ( 2.1 ) See Preparation and Dilution Technique for instructions on BOTOX reconstitution, storage, and preparation before injection ( 2.2 ) Overactive Bladder: Recommended total dose 100 Units, as 0.5 mL (5 Units) injections across 20 sites into the detrusor ( 2.3 ) Adult Detrusor Overactivity associated with a Neurologic Condition: Recommended total dose 200 Units, as 1 mL (~6.7 Units) injections across 30 sites into the detrusor ( 2.3 ) Pediatric Detrusor Overactivity associated with a Neurologic Condition: 0.5 mL injections across 20 sites into the detrusor ( 2.4 ) • Greater than or equal to 34 kg: Recommended total dose is 200 Units • Less than 34 kg: Recommended total dose is 6 Units/kg Chronic Migraine: Recommended total dose 155 Units, as 0.1 mL (5 Units) injections per each site divided across 7 head/neck muscles ( 2.5 ) Adult Upper Limb Spasticity: Recommended total dose up to 400 Units divided among affected muscles ( 2.6 ) Adult Lower Limb Spasticity: Recommended total dose 300 Units to 400 Units divided across ankle and toe muscles ( 2.6 ) Pediatric Upper Limb Spasticity: Recommended total dose 3 Units/kg to 6 Units/kg (maximum 200 Units) divided among affected muscles ( 2.7 ) Pediatric Lower Limb Spasticity: Recommended total dose 4 Units/kg to 8 Units/kg (maximum 300 Units) divided among affected muscles ( 2.7 ) Cervical Dystonia: Base dosing on the patient’s head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history; use lower initial dose in botulinum toxin naïve patients ( 2.8 ) Axillary Hyperhidrosis: 50 Units per axilla ( 2.9 ) Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected eye ( 2.10 ) Strabismus: The dose is based on prism diopter correction or previous response to treatment with BOTOX ( 2.11 ) 2.1 Instructions for Safe Use The potency Units of BOTOX (onabotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions ( 5.2 ) and Description ( 11 )] . Indication specific dosage and administration recommendations should be followed. When initiating treatment, the lowest recommended dose should be used. In treating adult patients for one or more indications, the maximum cumulative dose should not exceed 400 Units, in a 3-month interval. In pediatric patients, the total dose should not exceed the lower of 10 Units/kg body weight or 340 Units, in a 3-month interval [see Dosage and Administration ( 2.7 )] . The safe and effective use of BOTOX depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. An understanding of standard electromyographic techniques is also required for treatment of strabismus, upper or lower limb spasticity, and may be useful for the treatment of cervical dystonia. Physicians administering BOTOX must understand the relevant neuromuscular and structural anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures and disease, especially when injecting near the lungs. Do not use BOTOX and contact AbbVie (1-800-678-1605) if: the tamper evident features on the carton appear to be broken or compromised, or the U.S. License number 1889 is not present on the vial label and carton labeling [see How Supplied/Storage and Handling ( 16 )] . 2.2 Preparation and Dilution Technique Prior to injection, reconstitute each vacuum-dried vial of BOTOX with only sterile, preservative-free 0.9% Sodium Chloride Injection, USP. Draw up the proper amount of diluent in the appropriate size syringe (see Table 1 , or for specific instructions for detrusor overactivity associated with a neurologic condition, see Section 2.3 ), and slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix BOTOX with the diluent by rotating the vial. Record the date and time of reconstitution on the space on the label. BOTOX should be administered within 24 hours after reconstitution. During this time period, unused reconstituted BOTOX should be stored in a refrigerator (2° to 8°C) for up to 24 hours until time of use. BOTOX vials are for single-dose only. Discard any unused portion. Table 1: Dilution Instructions for BOTOX Vials (100 Units and 200 Units)** Diluent* Added to 100 Unit Vial Resulting Dose Units per 0.1 mL Diluent* Added to 200 Unit Vial Resulting Dose Units per 0.1 mL 1 mL 2 mL 4 mL 8 mL 10 mL 10 Units 5 Units 2.5 Units 1.25 Units 1 Unit 1 mL 2 mL 4 mL 8 mL 10 mL 20 Units 10 Units 5 Units 2.5 Units 2 Units *Preservative-free 0.9% Sodium Chloride Injection, USP Only **For Detrusor Overactivity associated with a Neurologic Condition Dilution, see Section 2.3 Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in the BOTOX dose is also possible by administering a smaller or larger injection volume - from 0.05 mL (50% decrease in dose) to 0.15 mL (50% increase in dose). An injection of BOTOX is prepared by drawing into an appropriately sized sterile syringe an amount of the properly reconstituted toxin slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe is attached to an appropriate injection needle. Patency of the needle should be confirmed. A new, sterile needle and syringe should be used to enter the vial on each occasion for removal of BOTOX. Reconstituted BOTOX should be clear, colorless, and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit. 2.3 Adult Bladder Dysfunction General Patients must not have a urinary tract infection (UTI) at the time of treatment. Prophylactic antibiotics, except aminoglycosides, [see Drug Interactions ( 7.1 )] should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment to reduce the likelihood of procedure-related UTI. Patients should discontinue anti-platelet therapy at least 3 days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding. Appropriate caution should be exercised when performing a cystoscopy. Overactive Bladder An intravesical instillation of diluted local anesthetic with or without sedation may be used prior to injection, per local site practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection. The recommended dose is 100 Units of BOTOX, and is the maximum recommended dose. The recommended dilution is 100 Units/10 mL with preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1 ). Dispose of any unused saline. Reconstituted BOTOX (100 Units/10 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided. The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injections (depending on the needle length) to remove any air. The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart (see Figure 1 ). For the final injection, approximately 1 mL of sterile normal saline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, patients should demonstrate their ability to void prior to leaving the clinic. The patient should be observed for at least 30 minutes post-injection and until a spontaneous void has occurred. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median time until patients qualified for the second treatment of BOTOX in double-blind, placebo-controlled clinical studies was 169 days [~24 weeks]), but no sooner than 12 weeks from the prior bladder injection. Figure 1 : Injection Pattern for Intradetrusor Injections for Treatment of Overactive Bladder and Detrusor Overactivity A ssociated with a Neurologic Condition Detrusor Overactivity associated with a Neurologic Condition An intravesical instillation of diluted local anesthetic with or without sedation, or general anesthesia may be used prior to injection, per local site practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection. The recommended dose is 200 Units of BOTOX per treatment, and should not be exceeded. 200 Unit Vial of BOTOX Reconstitute a 200 Unit vial of BOTOX with 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vial gently. Draw 2 mL from the vial into each of three 10 mL syringes. Complete the reconstitution by adding 8 mL of preservative-free 0.9% Sodium Chloride Injection, USP into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. 100 Unit Vial of BOTOX Reconstitute two 100 Unit vials of BOTOX, each with 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vials gently. Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe for a total of 4 mL in each syringe. Complete the reconstitution by adding 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. Reconstituted BOTOX (200 Units/30 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided. The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injections (depending on the needle length) to remove any air. The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of 1 mL (~6.7 Units) each (total volume of 30 mL) should be spaced approximately 1 cm apart (see Figure 1 ). For the final injection, approximately 1 mL of sterile normal saline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 minutes post-injection. Patients should be considered for re-injection when the clinical effect of the previous injection diminishes (median time to qualification for re-treatment in the double-blind, placebo-controlled clinical studies was 295-337 days [42-48 weeks] for BOTOX 200 Units), but no sooner than 12 weeks from the prior bladder injection. Figure 1: Injection Pattern for Intradetrusor Injections for Treatment of Overactive Bladder and Detrusor Overactivity associated with a Neurologic Condition 2.4 Pediatric Detrusor Overactivity A ssociated with a Neurologic Condition Patients must not have a urinary tract infection (UTI) at the time of treatment. Oral prophylactic antibiotics, except aminoglycosides, [see Drug Interactions ( 7.1 )] should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment to reduce the likelihood of procedure-related UTI. Alternatively, for patients receiving general anesthesia (or conscious sedation) for the treatment of detrusor overactivity associated with a neurologic condition, one dose of IV prophylactic antibiotics, except aminoglycosides, [see Drug Interactions ( 7.1 )] may be administered prior to treatment administration on the day of treatment. Patients should discontinue anti-platelet therapy at least 3 days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding. Appropriate caution should be exercised when performing a cystoscopy. In patients 5 years to less than 12 years of age: Consider general anesthesia (or conscious sedation) prior to injection, per local site practice. In patients 12 years of age or older: Consider an intravesical instillation of diluted local anesthetic with or without sedation, or general anesthesia prior to injection, per local site practice. At a minimum, consider a diluted instillation of local anesthetic for all age groups. If a local anesthetic instillation is performed, drain and irrigate the bladder with sterile saline before injection. If patient’s body weight is greater than or equal to 34 kg, the recommended dosage is 200 Units of BOTOX per treatment administered as an intradetrusor injection after dilution: Reconstitute BOTOX to result in 20 Units BOTOX/mL in the vial(s): ◦ BOTOX 200 Unit vial: add 10 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vial gently. ◦ BOTOX 100 Unit vials: add 5 mL of preservative-free 0.9% Sodium Chloride Injection, USP to each of two 100 Unit vials of BOTOX and mix the vials gently. Draw 10 mL from the vial(s) into one 10 mL dosing syringe. Use immediately after reconstitution in the syringe. Dispose of any unused saline. If patient’s body weight is less than 34 kg, the recommended dosage is 6 Units/kg body weight administered as a bladder injection after dilution (refer to Table 2): Reconstitute BOTOX to result in 20 Units BOTOX/mL in the vial(s): ◦ BOTOX 200 Unit vial: add 10 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vial gently. ◦ BOTOX 100 Unit vial(s): add 5 mL of preservative-free 0.9% Sodium Chloride Injection, USP to one 100 Unit vial of BOTOX (if final dose is less than or equal to 100 U) or to each of two 100 Unit vials of BOTOX (if final dose is greater than 100 U) and mix the vial(s) gently. Refer to Table 2 for dilution instructions (i.e., the amount of reconstituted BOTOX and additional diluent to draw into one 10 mL dosing syringe). Use BOTOX immediately after reconstitution in the syringe. Dispose of any unused preservative-free 0.9% Sodium Chloride Injection, USP. Table 2: BOTOX Dilution Instructions and Final Dosing for Patients with Body Weight < 34 kg Body Weight (kg) Volume of reconstituted BOTOX and Diluent * (mL) to draw into dosing syringe to achieve a final volume of 10 mL Final dose of BOTOX in dosing syringe BOTOX (mL) Diluent* (mL) 12 to less than 14 3.6 6.4 72 Units 14 to less than 16 4.2 5.8 84 Units 16 to less than 18 4.8 5.2 96 Units 18 to less than 20 5.4 4.6 108 Units 20 to less than 22 6 4 120 Units 22 to less than 24 6.6 3.4 132 Units 24 to less than 26 7.2 2.8 144 Units 26 to less than 28 7.8 2.2 156 Units 28 to less than 30 8.4 1.6 168 Units 30 to less than 32 9 1 180 Units 32 to less than 34 9.6 0.4 192 Units *Preservative-free 0.9% Sodium Chloride Injection, USP Only Reconstituted BOTOX is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided. The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injections (depending on the needle length) to remove any air. The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart (see Figure 1 ). For the final injection, approximately 1 mL of sterile normal saline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 minutes post-injection. Patients should be considered for re-injection when the clinical effect of the previous injection diminishes (median time to qualification for re-treatment in the double-blind, parallel group clinical study was 207 days [30 weeks] for BOTOX 200 Units), but no sooner than 12 weeks from the prior bladder injection. 2. 5 Chronic Migraine The recommended dilution is 200 Units/4 mL or 100 Units/2 mL, with a final concentration of 5 Units per 0.1 mL (see Table 1 ). The recommended dose for treating chronic migraine is 155 Units administered intramuscularly using a sterile 30-gauge, 0.5 inch needle as 0.1 mL (5 Units) injections per each site. Injections should be divided across 7 specific head/neck muscle areas as specified in the diagrams and Table 3 below. A one inch needle may be needed in the neck region for patients with thick neck muscles. With the exception of the procerus muscle, which should be injected at one site (midline), all muscles should be injected bilaterally with half the number of injection sites administered to the left, and half to the right side of the head and neck. The recommended re-treatment schedule is every 12 weeks. Diagrams 1-4: Recommended Injection Sites (A through G) for Chronic Migraine Table 3: BOTOX Dosing by Muscle for Chronic Migraine Head/Neck Area Recommended Dose (Number of Sites a ) Frontalis b 20 Units divided in 4 sites Corrugator b 10 Units divided in 2 sites Procerus 5 Units in 1 site Occipitalis b 30 Units divided in 6 sites Temporalis b 40 Units divided in 8 sites Trapezius b 30 Units divided in 6 sites Cervical Paraspinal Muscle Group b 20 Units divided in 4 sites Total Dose: 155 Units divided in 31 sites a Each IM injection site = 0.1 mL = 5 Units BOTOX b Dose distributed bilaterally Diagrams 1-4: Recommended Injection Sites (A through G) for Chronic Migraine 2. 6 Adult Spasticity General Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient’s response to previous treatment, or adverse event history with BOTOX. The recommended dilution is 200 Units/4 mL or 100 Units/2 mL with preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1 ). The lowest recommended starting dose should be used, and no more than 50 Units per site should generally be administered. An appropriately sized needle (e.g., 25-30 gauge) may be used for superficial muscles, and a longer 22 gauge needle may be used for deeper musculature. Localization of the involved muscles with techniques such as needle electromyographic guidance, nerve stimulation, or ultrasound is recommended. Repeat BOTOX treatment may be administered when the effect of a previous injection has diminished, but generally no sooner than 12 weeks after the previous injection. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of BOTOX and muscles to be injected. Adult Upper Limb Spasticity In clinical trials, doses ranging from 75 Units to 400 Units were divided among selected muscles (see Table 4 and Figure 2 ) at a given treatment session. Table 4: BOTOX Dosing by Muscle for Adult Upper Limb Spasticity Muscle Recommended Dose Total Dosage (Number of Sites) Biceps Brachii 60 Units to 200 Units divided in 2 to 4 sites Brachioradialis 45 Units to 75 Units divided in 1 to 2 sites Brachialis 30 Units to 50 Units divided in 1 to 2 sites Pronator Teres 15 Units to 25 Units in 1 site Pronator Quadratus 10 Units to 50 Units in 1 site Flexor Carpi Radialis 12.5 Units to 50 Units in 1 site Flexor Carpi Ulnaris 12.5 Units to 50 Units in 1 site Flexor Digitorum Profundus 30 Units to 50 Units in 1 site Flexor Digitorum Sublimis 30 Units to 50 Units in 1 site Lumbricals/Interossei 5 Units to 10 Units in 1 site Adductor Pollicis 20 Units in 1 site Flexor Pollicis Longus 20 Units in 1 site Flexor pollicis brevis/ Opponens pollicis 5 Units to 25 Units in 1 site Figure 2 : Injection Sites for Adult Upper Limb Spasticity Adult Lower Limb Spasticity The recommended dose for treating adult lower limb spasticity is 300 Units to 400 Units divided among 5 muscles (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus and flexor digitorum longus) (see Table 5 and Figure 3 ). Table 5: BOTOX Dosing by Muscle for Adult Lower Limb Spasticity Muscl e Recommended Dose Total Dosage (Number of Sites) Gastrocnemius medial head 75 Units divided in 3 sites Gastrocnemius lateral head 75 Units divided in 3 sites Soleus 75 Units divided in 3 sites Tibialis Posterior 75 Units divided in 3 sites Flexor hallucis longus 50 Units divided in 2 sites Flexor digitorum longus 50 Units divided in 2 sites Figure 3 : Inj e ction Sites for Adult Lower Limb Spa s t icity A close up of a piece of paper Description automatically generated Figure 3: Injection Sites for Adult Lower Limb Spasticity 2. 7 Pediatric Spasticity General Localization of the involved muscles with techniques such as needle electromyographic guidance, nerve stimulation, or ultrasound is recommended. When treating both lower limbs or the upper and lower limbs in combination, the total dose should not exceed the lower of 10 Units/kg body weight or 340 Units, in a 3-month interval [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.6 )] . Additional general adult spasticity dosing information is also applicable to pediatric spasticity patients [see Dosage and Administration ( 2.6 )] . Pediatric Upper Limb Spasticity The recommended dose for treating pediatric upper limb spasticity is 3 Units/kg to 6 Units/kg divided among the affected muscles (see Table 6 and Figure 4 ). The total dose of BOTOX administered per treatment session in the upper limb should not exceed 6 Units/kg or 200 Units, whichever is lower. Table 6: BOTOX Dosing by Muscle for Pediatric Upper Limb Spasticity Muscle Recommended Dose and Number of Sites Biceps Brachii 1.5 Units/kg to 3 Units/kg divided in 4 sites Brachialis 1 Unit/kg to 2 Units/kg divided in 2 sites Brachioradialis 0.5 Units/kg to 1 Unit/kg divided in 2 sites Flexor Carpi Radialis 1 Unit/kg to 2 Units/kg divided in 2 sites Flexor Carpi Ulnaris 1 Unit/kg to 2 Units/kg divided in 2 sites Flexor Digitorum Profundus 0.5 Units/kg to 1 Unit/kg divided in 2 sites Flexor Digitorum Sublimis 0.5 Units/kg to 1 Unit/kg divided in 2 sites Figure 4: Injection Sites for Pediatric Upper Limb Spasticity Pediatric Lower Limb Spasticity The recommended dose for treating pediatric lower limb spasticity is 4 Units/kg to 8 Units/kg divided among the affected muscles (see Table 7 and Figure 5 ). The total dose of BOTOX administered per treatment session in the lower limb should not exceed 8 Units/kg or 300 Units, whichever is lower. Table 7: BOTOX Dosing by Muscle for Pediatric Lower Limb Spasticity Muscl e Recommend e d Dose Total Dosage (Number of Sites) Gastrocnemius medial head 1 Unit/kg to 2 Units/kg divided in 2 sites Gastrocnemius lateral head 1 Unit/kg to 2 Units/kg divided in 2 sites Soleus 1 Unit/kg to 2 Units/kg divided in 2 sites Tibialis Posterior 1 Unit/kg to 2 Units/kg divided in 2 sites Figure 5 : Injection Sites for Pediatric Lower Limb Spasticity Figure 4: Injection Sites for Pediatric Upper Limb Spasticity Figure 5 2. 8 Cervical Dystonia A double-blind, placebo-controlled study enrolled patients who had extended histories of receiving and tolerating BOTOX injections, with prior individualized adjustment of dose. The mean BOTOX dose administered to patients in this study was 236 Units (25th to 75th percentile range of 198 Units to 300 Units). The BOTOX dose was divided among the affected muscles [see Clinical Studies ( 14.7 )]. Dosing in initial and sequential treatment sessions should be tailored to the individual patient based on the patient’s head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history. The initial dose for a patient without prior use of BOTOX should be at a lower dose, with subsequent dosing adjusted based on individual response. Limiting the total dose injected into the sternocleidomastoid muscle to 100 Units or less may decrease the occurrence of dysphagia [see Warnings and Precautions ( 5.1 , 5.5 , 5.6 )]. The recommended dilution is 200 Units/2 mL, 200 Units/4 mL, 100 Units/1 mL, or 100 Units/2 mL with preservative-free 0.9% Sodium Chloride Injection, USP, depending on volume and number of injection sites desired to achieve treatment objectives (see Table 1 ). In general, no more than 50 Units per site should be administered using a sterile needle (e.g., 25-30 gauge) of an appropriate length. Localization of the involved muscles with electromyographic guidance may be useful. Clinical improvement generally begins within the first two weeks after injection with maximum clinical benefit at approximately six weeks post-injection. In the double-blind, placebo-controlled study most subjects were observed to have returned to pre-treatment status by 3 months post-treatment. 2. 9 Primary Axillary Hyperhidrosis The recommended dose is 50 Units per axilla. The hyperhidrotic area to be injected should be defined using standard staining techniques, e.g., Minor’s Iodine-Starch Test. The recommended dilution is 100 Units/4 mL with preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1 ). Using a sterile 30 gauge needle, 50 Units of BOTOX (2 mL) is injected intradermally in 0.1 to 0.2 mL aliquots to each axilla evenly distributed in multiple sites (10-15) approximately 1-2 cm apart. Repeat injections for hyperhidrosis should be administered when the clinical effect of a previous injection diminishes. Instructions for the Minor’s Iodine-Starch Test Procedure: Patients should shave underarms and abstain from use of over-the-counter deodorants or antiperspirants for 24 hours prior to the test. Patient should be resting comfortably without exercise or hot drinks for approximately 30 minutes prior to the test. Dry the underarm area and then immediately paint it with iodine solution. Allow the area to dry, then lightly sprinkle the area with starch powder. Gently blow off any excess starch powder. The hyperhidrotic area will develop a deep blue-black color over approximately 10 minutes. Each injection site has a ring of effect of up to approximately 2 cm in diameter. To minimize the area of no effect, the injection sites should be evenly spaced as shown in Figure 6. Figure 6 : Injection Pattern for Primary Axillary Hyperhidrosis Each dose is injected to a depth of approximately 2 mm and at a 45° angle to the skin surface, with the bevel side up to minimize leakage and to ensure the injections remain intradermal. If injection sites are marked in ink, do not inject BOTOX directly through the ink mark to avoid a permanent tattoo effect. Figure 6: Injection Pattern for Primary Axillary Hyperhidrosis 2. 10 Blepharospasm For blepharospasm, reconstituted BOTOX is injected using a sterile, 27-30 gauge needle without electromyographic guidance. The initial recommended dose is 1.25 Units-2.5 Units (0.05 mL to 0.1 mL volume at each site) injected into the medial and lateral pre-tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid. Avoiding injection near the levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia. Ecchymosis occurs easily in the soft eyelid tissues. This can be prevented by applying pressure at the injection site immediately after the injection. The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5 Units it is 100 Units/4 mL (see Table 1 ). In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient, usually defined as an effect that does not last longer than two months. However, there appears to be little benefit obtainable from injecting more than 5 Units per site. Some tolerance may be found when BOTOX is used in treating blepharospasm if treatments are given any more frequently than every three months, and is rare to have the effect be permanent. The cumulative dose of BOTOX treatment for blepharospasm in a 30-day period should not exceed 200 Units. 2. 1 1 Strabismus BOTOX is intended for injection into extraocular muscles utilizing the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle. Injection without surgical exposure or electromyographic guidance should not be attempted. Physicians should be familiar with electromyographic technique. To prepare the eye for BOTOX injection, it is recommended that several drops of a local anesthetic and an ocular decongestant be given several minutes prior to injection. The volume of BOTOX injected for treatment of strabismus should be between 0.05-0.15 mL per muscle. The initial listed doses of the reconstituted BOTOX [see Dosage and Administration ( 2.2 )] typically create paralysis of the injected muscles beginning one to two days after injection and increasing in intensity during the first week. The paralysis lasts for 2-6 weeks and gradually resolves over a similar time period. Overcorrections lasting over six months have been rare. About one half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose, or because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilize the alignment. Initial D oses in Units Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations. For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1.25 Units-2.5 Units in any one muscle. For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2.5 Units-5 Units in any one muscle. For persistent VI nerve palsy of one month or longer duration: 1.25 Units-2.5 Units in the medial rectus muscle. Subsequent D oses for R esidual or R ecurrent S trabismus It is recommended that patients be re-examined 7-14 days after each injection to assess the effect of that dose. Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose. Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to two-fold compared to the previously administered dose. Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles. The maximum recommended dose as a single injection for any one muscle is 25 Units. The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5 Units it is 100 Units/4 mL (see Table 1 ).

BOTOX is contraindicated: In patients who are hypersensitive to any botulinum toxin product or to any of the components in the formulation [see Warnings and Precautions ( 5.4 )] . In the presence of infection at the proposed injection site(s). For intradetrusor injection in patients with a urinary tract infection; or in patients with urinary retention or post-void residual (PVR) urine volume >200 mL who are not routinely performing clean intermittent self-catheterization (CIC) [see Warnings and Precautions ( 5.12 , 5.13 )] . Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation ( 4 , 5.4 , 6 ) Infection at the proposed injection site ( 4 ) Intradetrusor Injections: Urinary tract infection or urinary retention ( 4 )

The following adverse reactions to BOTOX (onabotulinumtoxinA) for injection are discussed in greater detail in other sections of the labeling: Spread of Toxin Effects [see Warnings and Precautions ( 5.1 )] Serious Adverse Reactions with Unapproved Use [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Contraindications ( 4 ) a nd Warnings and Precautions ( 5.4 )] Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders [see Warnings and Precautions ( 5.5 )] Dysphagia and Breathing Difficulties [see Warnings and Precautions ( 5.6 )] Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity Associated with a Neurologic Condition [see Warnings and Precautions ( 5.7 )] Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm [see Warnings and Precautions ( 5.8 )] Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus [see Warnings and Precautions ( 5.9 )] Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity [se e Warnings and Precautions ( 5.10 )] Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity Associated with a Neurologic Condition [see Warnings and Precautions ( 5.11 )] Urinary Tract Infections in Patients with Overactive Bladder [see Warnings and Precautions ( 5.12 )] Urinary Retention in Patients Treated for Bladder Dysfunction [see Warnings and Precautions ( 5.13 )] The most common adverse reactions (≥5% and >placebo, if applicable) are ( 6.1 ): OAB: urinary tract infection, dysuria, urinary retention Adult Detrusor Overactivity associated with a neurologic condition: urinary tract infection, urinary retention Pediatric Detrusor Overactivity associated with a neurologic condition: urinary tract infection, leukocyturia, bacteriuria Chronic Migraine: neck pain, headache Adult Spasticity: pain in extremity Pediatric Spasticity: upper respiratory tract infection Cervical Dystonia: dysphagia, upper respiratory infection, neck pain, headache, increased cough, flu syndrome, back pain, rhinitis Axillary Hyperhidrosis: injection site pain and hemorrhage, non-axillary sweating, pharyngitis, flu syndrome To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, but with different labeled Indications and Usage. Therefore, adverse reactions observed with the use of BOTOX Cosmetic also have the potential to be observed with the use of BOTOX. In general, adverse reactions occur within the first week following injection of BOTOX and, while generally transient, may have a duration of several months or longer. Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising may be associated with the injection. Symptoms associated with flu-like symptoms (e.g., nausea, fever, myalgia) have been reported after treatment. Needle-related pain and/or anxiety may result in vasovagal responses (including syncope, hypotension), which may require appropriate medical therapy. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of nearby muscles may also occur due to spread of toxin [see Warnings and Precautions ( 5.1 )] . Overactive Bladder Table 14 presents the most frequently reported adverse reactions in double-blind, placebo-controlled clinical trials for overactive bladder occurring within 12 weeks of the first BOTOX treatment. Table 14: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Often than in Placebo-Treated Patients Within the First 12 Weeks after Intradetrusor Injection, in Double-Blind, Placebo-Controlled Clinical Trials in Patients with OAB Adverse Reactions BOTOX 100 Units (N=552) % Placebo (N=542) % Urinary tract infection Dysuria Urinary retention Bacteriuria Residual urine volume* 18 9 6 4 3 6 7 0 2 0 *Elevated PVR not requiring catheterization. Catheterization was required for PVR ≥350 mL regardless of symptoms, and for PVR ≥200 mL to <350 mL with symptoms (e.g., voiding difficulty). A higher incidence of urinary tract infection was observed in patients with diabetes mellitus treated with BOTOX 100 Units and placebo than in patients without diabetes, as shown in Table 15. Table 15: Proportion of Patients Experiencing Urinary Tract Infection Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials in OAB According to History of Diabetes Mellitus Patients with Diabet es Patients without D iabet es B OTOX 100 Units (N=81) % Placebo (N=69) % B OTOX 100 Units (N=526) % Placebo (N=516) % Urinary tract infection (UTI) 31 12 26 10 The incidence of UTI increased in patients who experienced a maximum post-void residual (PVR) urine volume ≥200 mL following BOTOX injection compared to those with a maximum PVR <200 mL following BOTOX injection, 44% versus 23%, respectively. No change was observed in the overall safety profile with repeat dosing during an open-label, uncontrolled extension trial. Adult Detrusor Overactivity associated with a Neurologic Condition Table 16 presents the most frequently reported adverse reactions in the double-blind, placebo-controlled studies within 12 weeks of injection for patients with detrusor overactivity associated with a neurologic condition treated with BOTOX 200 Units. Table 16: Adverse Reactions Reported by ≥2% of BOTOX-Treated Patients and More Frequent than in Placebo-Treated Patients Within the First 12 Weeks after Intradetrusor Injection in Double-Blind, Placebo-Controlled Clinical Trials Adverse Reactions BOTOX 200 Units (N=262) % Placebo (N=272) % Urinary tract infection Urinary retention Hematuria 24 17 4 17 3 3 The following adverse reactions with BOTOX 200 Units were reported at any time following initial injection and prior to re-injection or study exit (median duration of exposure was 44 weeks): urinary tract infections (49%), urinary retention (17%), constipation (4%), muscular weakness (4%), dysuria (4%), fall (3%), gait disturbance (3%), and muscle spasm (2%). In the Multiple Sclerosis (MS) patients enrolled in the double-blind, placebo-controlled trials, the MS exacerbation annualized rate (i.e., number of MS exacerbation events per patient-year) was 0.23 for BOTOX and 0.20 for placebo. No change was observed in the overall safety profile with repeat dosing. Table 17 presents the most frequently reported adverse reactions in a placebo-controlled, double-blind post-approval 52 week study with BOTOX 100 Units (Study NDO-3) conducted in MS patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition. These patients were not adequately managed with at least one anticholinergic agent and not catheterized at baseline. The table below presents the most frequently reported adverse reactions within 12 weeks of injection. Table 17: Adverse Reactions Reported in a Post Approval Study (NDO-3) by >2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients Within the First 12 Weeks after Intradetrusor Injection Adverse Reactions BOTOX 100 Unit s (N=66) % Placebo (N=78) % Urinary tract infection Bacteriuria Urinary retention Dysuria Residual urine volume* 26 9 15 5 17 6 5 1 1 1 * Elevated PVR not requiring catheterization. Catheterization was required for PVR ≥350 mL regardless of symptoms, and for PVR ≥200 mL to <350 mL with symptoms (e.g., voiding difficulty). The following adverse events with BOTOX 100 Units were reported at any time following initial injection and prior to re-injection or study exit (median duration of exposure was 51 weeks): urinary tract infections (39%), bacteriuria (18%), urinary retention (17%), residual urine volume* (17%), dysuria (9%), and hematuria (5%). No difference in the MS exacerbation annualized rate (i.e., number of MS exacerbating events per patient-year) was observed (BOTOX =0, placebo =0.07). Pediatric Detrusor Overactivity associated with a Neurologic Condition Table 18 presents the most frequently reported adverse reactions in Study 191622-120, a double-blind, parallel-group study conducted in pediatric patients with detrusor overactivity associated with a neurologic condition. These patients were not adequately managed with at least one anticholinergic agent and were using clean intermittent catheterization at baseline [see Clinical Studies ( 14.3 )]. The table below presents the most frequently reported adverse reactions during the 12 weeks following intradetrusor administration of BOTOX 200 Units. Table 18: Adverse Reactions Reported by ≥ 3% of BOTOX Treated Pediatric Patients within the First 12 Weeks after Intradetrusor Injection, Study 191622-120 Adverse Reactions BOTOX 200 Unit (N=30) Urinary tract infection 2 (7%) Bacteriuria 6 (20%) Leukocyturia 2 (7%) Hematuria 1 (3%) No change was observed in the overall safety profile with repeat dosing. The most common adverse reactions in patients who received BOTOX 6 U/kg and less than a total dose of 200 U in Study 191622-120 were urinary tract infection (UTI), bacteriuria and hematuria. Chronic Migraine In double-blind, placebo-controlled chronic migraine efficacy trials (Study 1 and Study 2), the discontinuation rate was 12% in the BOTOX treated group and 10% in the placebo-treated group. Discontinuations due to an adverse event were 4% in the BOTOX group and 1% in the placebo group. The most frequent adverse events leading to discontinuation in the BOTOX group were neck pain, headache, worsening migraine, muscular weakness and eyelid ptosis. The most frequently reported adverse reactions following injection of BOTOX for chronic migraine appear in Table 19. Table 19: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Two Chronic Migraine Double-Blind, Placebo-Controlled Clinical Trials Adverse Reactions BOTOX 155 Units-195 Units (N=687) % Placebo (N=692) % Nervous system disorders Headache Migraine Facial paresis 5 4 2 3 3 0 Eye disorders Eyelid ptosis 4 <1 Infections and Infestations Bronchitis 3 2 Musculoskeletal and connective tissue disorders Neck pain Musculoskeletal stiffness Muscular weakness Myalgia Musculoskeletal pain Muscle spasms 9 4 4 3 3 2 3 1 <1 1 1 1 General disorders and administration site conditions Injection site pain 3 2 Vascular Disorders Hypertension 2 1 Other adverse reactions that occurred more frequently in the BOTOX group compared to the placebo group at a frequency less than 1% and potentially BOTOX related include: vertigo, dry eye, eyelid edema, dysphagia, eye infection, and jaw pain. Severe worsening of migraine requiring hospitalization occurred in approximately 1% of BOTOX treated patients in Study 1 and Study 2, usually within the first week after treatment, compared to 0.3% of placebo-treated patients. Adult Upper Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX for adult upper limb spasticity appear in Table 20. Table 20: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Adult Upper Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trials Adverse Reactions BOTOX 251 Units - 360 Units (N=115) % BOTOX 150 Units - 250 Units (N=188) % BOTOX <150 Units (N=54) % Placebo (N=182) % Gastrointestinal disorder Nausea 3 2 2 1 General disorders and administration site conditions Fatigue 3 2 2 0 Infections and infestations Bronchitis 3 2 0 1 Musculoskeletal and connective tissue disorders Pain in extremity Muscular weakness 6 0 5 4 9 2 4 1 Twenty-two adult patients, enrolled in double-blind placebo controlled studies, received 400 Units or higher of BOTOX for treatment of upper limb spasticity. In addition, 44 adults received 400 Units of BOTOX or higher for four consecutive treatments over approximately one year for treatment of upper limb spasticity. The type and frequency of adverse reactions observed in patients treated with 400 Units of BOTOX were similar to those reported in patients treated for upper limb spasticity with 360 Units of BOTOX. Adult Lower Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX for adult lower limb spasticity appear in Table 21. Two hundred thirty-one patients enrolled in a double-blind placebo controlled study (Study 7) received 300 Units to 400 Units of BOTOX, and were compared with 233 patients who received placebo. Patients were followed for an average of 91 days after injection. Table 21: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Adult Lower Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 7) Adverse Reactions B OTOX (N=231) % Placebo (N=233) % Musculoskeletal and connective tissue disorders Arthralgia Back pain Myalgia 3 3 2 1 2 1 Infections and infestations Upper respiratory tract infection 2 1 General disorders and administration site conditions Injection site pain 2 1 Pediatric Upper Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX in pediatric patients 2 to 17 years of age with upper limb spasticity appear in Table 22. In a double-blind, placebo-controlled trial (Study 1), 78 patients were treated with 3 Units/kg of BOTOX, and 77 patients received 6 Units/kg to a maximum dose of 200 Units of BOTOX, and were compared to 79 patients who received placebo [see Clinical Studies ( 14.6 )]. Patients were followed for an average of 91 days after injection. Table 22: Adverse Reactions Reported by ≥2% of BOTOX 6 Units/kg Treated Patients and More Frequent than in Placebo-Treated Patients in Pediatric Upper Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 1) Adverse Reactions BOTOX 6 Units/kg (N= 77 ) % BOTOX 3 Units/kg (N= 78 ) % Placebo (N=79) % Infections and infestations Upper respiratory tract infection * 17 10 9 General disorders and administration site conditions Injection site pain 4 3 1 Gastrointestinal disorders Nausea Constipation 4 3 0 0 0 1 Respiratory, thoracic and mediastinal disorders Rhinorrhea Nasal congestion 4 3 0 0 1 1 Nervous system disorders Seizure ** 5 1 0 * Includes upper respiratory tract infection and viral upper respiratory tract infection ** Includes seizure and partial seizure Pediatric Lower Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX in pediatric patients 2 to 17 years of age with lower limb spasticity appear in Table 23. In a double-blind, placebo-controlled trial (Study 2), 126 patients were treated with 4 Units/kg of BOTOX, and 128 patients received 8 Units/kg to a maximum dose of 300 Units of BOTOX, and were compared to 128 patients who received placebo [see Clinical Studies ( 14.6 ) ]. Patients were followed for an average of 89 days after injection. Table 23: Adverse Reactions Reported by ≥2% of BOTOX 8 Units/kg Treated Patients and More Frequent than in Placebo-Treated Patients in Pediatric Lower Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 2) Adverse Reactions BOTOX 8 Units/kg (N=128) % BOTOX 4 Units/kg (N=126) % Placebo (N=128) % General disorders and administration site conditions Injection site erythema Injection site pain 2 2 0 2 0 0 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 2 0 1 Injury, poisoning and procedural complications Ligament sprain Skin abrasion 2 2 1 0 0 0 Metabolism and nutrition disorders Decreased appetite 2 0 0 Cervical Dystonia In cervical dystonia patients evaluated for safety in double-blind and open-label studies following injection of BOTOX, the most frequently reported adverse reactions were dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%). Other events reported in 2-10% of patients in any one study in decreasing order of incidence include: increased cough, flu syndrome, back pain, rhinitis, dizziness, hypertonia, soreness at injection site, asthenia, oral dryness, speech disorder, fever, nausea, and drowsiness. Stiffness, numbness, diplopia, ptosis, and dyspnea have been reported. Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of BOTOX resulting from the spread of the toxin outside the injected muscles [see Warning s and Precautions ( 5.1 , 5.6 )] . The most common severe adverse reaction associated with the use of BOTOX injection in patients with cervical dystonia is dysphagia with about 20% of these cases also reporting dyspnea [see Wa rnings and Precautions ( 5.1 , 5.6 )] . Most dysphagia is reported as mild or moderate in severity. However, it may be associated with more severe signs and symptoms [s ee Warnings and Precautions ( 5.6 )] . Additionally, reports in the literature include a case of a female patient who developed brachial plexopathy two days after injection of 120 Units of BOTOX for the treatment of cervical dystonia, and reports of dysphonia in patients who have been treated for cervical dystonia. Primary Axillary Hyperhidrosis The most frequently reported adverse reactions (3-10% of adult patients) following injection of BOTOX in double-blind studies included injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety. The data reflect 346 patients exposed to BOTOX 50 Units and 110 patients exposed to BOTOX 75 Units in each axilla. Blepharospasm In a study of blepharospasm patients who received an average dose per eye of 33 Units (injected at 3 to 5 sites) of the currently manufactured BOTOX, the most frequently reported adverse reactions were ptosis (21%), superficial punctate keratitis (6%), and eye dryness (6%). Other events reported in prior clinical studies in decreasing order of incidence include: irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia, entropion, diffuse skin rash, and local swelling of the eyelid skin lasting for several days following eyelid injection. In two cases of VII nerve disorder, reduced blinking from BOTOX injection of the orbicularis muscle led to serious corneal exposure, persistent epithelial defect, corneal ulceration and a case of corneal perforation. Focal facial paralysis, syncope, and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm. Strabismus Extraocular muscles adjacent to the injection site can be affected, causing vertical deviation, especially with higher doses of BOTOX. The incidence rates of these adverse effects in 2058 adults who received a total of 3650 injections for horizontal strabismus was 17%. The incidence of ptosis has been reported to be dependent on the location of the injected muscles, 1% after inferior rectus injections, 16% after horizontal rectus injections and 38% after superior rectus injections. In a series of 5587 injections, retrobulbar hemorrhage occurred in 0.3% of cases. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to onabotulinumtoxinA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In a long term, open-label study evaluating 326 cervical dystonia patients treated for an average of 9 treatment sessions with the current formulation of BOTOX, 4 (1.2%) patients had positive antibody tests. All 4 of these patients responded to BOTOX therapy at the time of the positive antibody test. However, 3 of these patients developed clinical resistance after subsequent treatment, while the fourth patient continued to respond to BOTOX therapy for the remainder of the study. One patient among the 445 hyperhidrosis patients (0.2%), two patients among the 380 adult upper limb spasticity patients (0.5%), and no patients among 406 migraine patients with analyzed specimens developed the presence of neutralizing antibodies. In one Phase 3 study and the open-label extension study in patients with pediatric lower limb spasticity, neutralizing antibodies developed in 2 of 264 patients (0.8%) treated with BOTOX for up to 5 treatment cycles. Both patients continued to experience clinical benefit following subsequent BOTOX treatments. In overactive bladder patients with analyzed specimens from the two phase 3 studies and the open-label extension study, neutralizing antibodies developed in 0 of 954 patients (0.0%) while receiving BOTOX 100 Unit doses and 3 of 260 patients (1.2%) after subsequently receiving at least one 150 Unit dose. Response to subsequent BOTOX treatment was not different following seroconversion in these three patients. In detrusor overactivity associated with neurologic condition patients with analyzable specimens in the adult drug development program (including the open-label extension study), neutralizing antibodies developed in 3 of 300 patients (1.0%) after receiving only BOTOX 200 Unit doses and 5 of 258 patients (1.9%) after receiving at least one 300 Unit dose. Following development of neutralizing antibodies in these 8 patients, 4 continued to experience clinical benefit, 2 did not experience clinical benefit, and the effect on the response to BOTOX in the remaining 2 patients is not known. In 99 pediatric patients who had a negative baseline result for binding antibodies or neutralizing antibodies and had at least one evaluable post-baseline value from one randomized double-blind study and one double-blind extension study, no patients developed neutralizing antibodies after receiving 50 Units to 200 Units of BOTOX. The data reflect the patients whose test results were considered positive for neutralizing activity to BOTOX in a mouse protection assay or negative based on a screening ELISA assay or mouse protection assay. Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin. The critical factors for neutralizing antibody formation have not been well characterized. The results from some studies suggest that BOTOX injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BOTOX. 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. These reactions include: abdominal pain; alopecia, including madarosis; anorexia; brachial plexopathy; denervation/muscle atrophy; diarrhea; dry eye; eyelid edema (following periocular injection); hyperhidrosis; hypoacusis; hypoaesthesia; localized muscle twitching; malaise; Mephisto sign; paresthesia; peripheral neuropathy; radiculopathy; erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption; strabismus; tinnitus; and visual disturbances. There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin [s ee Warnings and Precautions ( 5.4 , 5.6 )]. There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been established. New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events. The exact relationship of these events to the botulinum toxin injection has not been established.

Patients receiving concomitant treatment of BOTOX and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents), or muscle relaxants, should be observed closely because the effect of BOTOX may be potentiated ( 7.1 , 7.4 ) 7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of BOTOX and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated. 7.2 Anticholinergic Drugs Use of anticholinergic drugs after administration of BOTOX may potentiate systemic anticholinergic effects. 7.3 Other Botulinum Neurotoxin Products The effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. 7.4 Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of BOTOX.

16.2 Storage and Handling Unopened vials of BOTOX should be stored in a refrigerator between 2° to 8°C (36º to 46ºF) for up to 36 months. Do not use after the expiration date on the vial. Reconstituted BOTOX may be stored in a refrigerator (2° to 8°C) for up to 24 hours until time of use [see Dosage and Administ r ation ( 2.2 )] .