botulinum toxin type A

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION 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 ) Figure 1: Injection Pattern for Intradetrusor Injections for Treatment of Overactive Bladder and Detrusor Overactivity associated with a Neurologic Condition Diagrams 1-4: Recommended Injection Sites (A through G) for Chronic Migraine A close up of a piece of paper Description automatically generated Figure 3: Injection Sites for Adult Lower Limb Spasticity Figure 4: Injection Sites for Pediatric Upper Limb Spasticity Figure 5 Figure 6: Injection Pattern for Primary Axillary Hyperhidrosis 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

WARNINGS AND PRECAUTIONS Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek immediate medical attention if respiratory, speech or swallowing difficulties occur ( 5.1 , 5.6 ) Potency Units of BOTOX are not interchangeable with other preparations of botulinum toxin products ( 5.2 , 11 ) Potential serious adverse reactions after BOTOX injections for unapproved uses ( 5.3 ) Concomitant neuromuscular disorder may exacerbate clinical effects of treatment ( 5.5 ) Use with caution in patients with compromised respiratory function ( 5.6 , 5.7 , 5.10 ) Corneal exposure and ulceration due to reduced blinking may occur with BOTOX treatment of blepharospasm ( 5.8 ) Retrobulbar hemorrhages and compromised retinal circulation may occur with BOTOX treatment of strabismus ( 5.9 ) Bronchitis and upper respiratory tract infections in patients treated for spasticity ( 5.10 ) Urinary tract infections in patients treated for OAB ( 5.12 ) Urinary retention: Post-void residual urine volume should be monitored in patients treated for OAB or adult detrusor overactivity associated with a neurologic condition who do not catheterize routinely, particularly patients with multiple sclerosis or diabetes mellitus. ( 5.13 ) 5. 1 Spread of Toxin Effect Postmarketing safety data from BOTOX and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, and particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia and spasticity. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders occur. No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX for blepharospasm at the recommended dose (30 Units and below), severe primary axillary hyperhidrosis at the recommended dose (100 Units), strabismus, or for chronic migraine at the labeled doses have been reported. 5.2 Lack of Interchangeability between Botulinum Toxin Products The potency Units of BOTOX 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 Description ( 11 )] . 5.3 Serious Adverse Reactions with Unapproved Use Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant spread of toxin, but may have resulted from the administration of BOTOX to the site of injection and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant disabilities. There is insufficient information to identify factors associated with an increased risk for adverse reactions associated with the unapproved uses of BOTOX. The safety and effectiveness of BOTOX for unapproved uses have not been established. 5.4 Hypersensitivity Reactions Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs, further injection of BOTOX should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined. 5.5 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given botulinum toxin. Patients with known or unrecognized neuromuscular disorders or neuromuscular junction disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from therapeutic doses of BOTOX [see Warnings and Precautions ( 5.1 , 5.6 ) ] . 5.6 Dysphagia and Breathing Difficulties Treatment with BOTOX and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing [see Warnings and Precautions ( 5.1 )]. Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several months, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised. Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been postmarketing reports of serious breathing difficulties, including respiratory failure. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscle for the treatment of cervical dystonia have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia. Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Warnings and Precautions ( 5.1 )] . 5.7 Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity Associated with a Neurologic Condition Patients with compromised respiratory status treated with BOTOX for spasticity should be monitored closely. In a double-blind, placebo-controlled, parallel group study in adult patients treated for upper limb spasticity with stable reduced pulmonary function (defined as FEV 1 40-80% of predicted value and FEV 1 /FVC ≤ 0.75), the event rate in change of Forced Vital Capacity (FVC) ≥15% or ≥20% was generally greater in patients treated with BOTOX than in patients treated with placebo (see Table 8 ). Table 8: Event Rate Per Patient Treatment Cycle Among Adult Upper Limb Spasticity Patients with Reduced Lung Function Who Experience

CONTRAINDICATIONS LETYBO is contraindicated in: Patients with known hypersensitivity to any botulinum toxin preparation or to any of the components in the LETYBO formulation [see Warnings and Precautions ( 5.4 )] . The presence of infection at the proposed injection site(s). Known hypersensitivity to any botulinum toxin preparation or to any of the components in the LETYBO formulation ( 4 ) Infection at the injection site ( 4 ) 4.1 Known Hypersensitivity to Botulinum Toxin BRANDNAME is contraindicated in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation [see Warnings and Precautions ( 5.4 )]. 4.2 Infection at the Injection Site(s) BRANDNAME is contraindicated in the presence of infection at the proposed injection site(s).

DRUG INTERACTIONS Concomitant use of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission or muscle relaxants, should be observed closely because effect of DYSPORT may be potentiated ( 7.1 , 7.4 ) Anticholinergic drugs may potentiate systemic anticholinergic effects ( 7.2 ) The effect of administering different botulinum neurotoxins during the course of treatment with DYSPORT is unknown ( 7.3 ) 7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents) should only be performed with caution because the effect of the botulinum toxin may be potentiated. If co-administered, observe the patient closely. 7.2 Anticholinergic Drugs Use of anticholinergic drugs after administration of DYSPORT may potentiate systemic anticholinergic effects such as blurred vision. 7.3 Other Botulinum Neurotoxin Products The effect of administering botulinum neurotoxin products including DYSPORT, at the same time or within several months of each other is unknown. Excessive weakness may be exacerbated by another administration of 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 DYSPORT.

ADVERSE REACTIONS 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 i

Mechanism of Action BOTOX blocks neuromuscular transmission by binding to acceptor sites on motor or autonomic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX. When injected intradermally, BOTOX produces temporary chemical denervation of the sweat gland resulting in local reduction in sweating. Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release.