BOTOX

1 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 …

2 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 ) 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 …

3 DOSAGE FORMS AND STRENGTHS For Injection: sterile 100 Units or 200 Units vacuum-dried powder in single-dose vials for reconstitution only with sterile, preservative-free 0.9% Sodium Chloride Injection, USP prior to injection. For Injection: 100 Units or 200 Units vacuum-dried powder in a single-dose vial ( 3 )

4 CONTRAINDICATIONS 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 )

6 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 b …

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary There are no studies or adequate data from postmarketing surveillance on the developmental risk associated with use of BOTOX in pregnant women. In animal studies, administration of BOTOX during pregnancy resulted in adverse effects on fetal growth (decreased fetal weight and skeletal ossification) at clinically relevant doses, which were associated with maternal toxicity [see Data ]. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Data Animal Data When BOTOX (4, 8, or 16 Units/kg) was administered intramuscularly to pregnant mice or rats two times during the period of organogenesis (on gestation days 5 and 13), reductions in fetal body weight and decreased fetal skeletal ossification were observed at the two highest doses. The no-effect dose for developmental toxicity in these studies (4 Units/kg) is approximately equal to the human dose of 400 Units, on a body weight basis (Units/kg). When BOTOX was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or 0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the two highest doses in rats and at the highest dose in rabbits. These doses were also associated with significant maternal toxicity, including abortions, early deliveries, and maternal death. The developmental no-effect doses in these studies of 1 Unit/kg in rats and 0.25 Units/kg in rabbits are less than the human dose of 400 Units, based on Units/kg. When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three different periods of development (prior to implantation, implantation, or organogenesis), no adverse effects on fetal development were observed. The developmental no-effect level for a single maternal dose in rats (16 Units/kg) is approximately 2 times the human dose of 400 Units, based on Units/kg. 8.2 Lactation Risk Summary There are no data on the presence of BOTOX in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BOTOX and any potential adverse effects on the breastfed infant from BOTOX or from the underlying maternal conditions. 8.4 Pediatric Use Detrusor Overactivity associated with a Neurologic Condition The safety and effectiveness of BOTOX for detrusor overactivity associated with a neurologic condition have been established in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. Use of BOTOX in this patient population is based on the results of a randomized, double-blind, parallel group trial in 113 pediatric patients 5 to 17 years of age (inclusive) with detrusor overactivity associated with a neurologic condition (Study 191622-120) and a long-term, multicenter, double-blind, long-term extension trial (Study 191622-121) [see Clinical Studies ( 14.3 )]. The most common adverse reactions in this population were urinary tract infection, bacteriuria, hematuria, and leukocyturia [see Adverse Reactions ( 6.1 ) ] . The safety and effectiveness of BOTOX have not been established in patients with NDO younger than 5 years of age. Overactive Bladder The safety and effectiveness of BOTOX for the treatment of overactive bladder have not been established in pediatric patients. Efficacy was not demonstrated in a multicenter, randomized, double-blind, parallel-group, multiple-dose clinical study which was conducted …

12.1 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.

11 DESCRIPTION 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; or 200 Units of Clostridium botulinum type A neurotoxin complex, 1 mg of Albumin Human, and 1.8 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.

10 OVERDOSAGE Excessive doses of BOTOX (onabotulinumtoxinA) for injection may be expected to produce neuromuscular weakness with a variety of symptoms. Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection or oral ingestion occur or overdose be suspected, the person should be medically supervised for several weeks for signs and symptoms of systemic muscular weakness which could be local, or distant from the site of injection [see Boxed Warning and Wa rnings and Precautions ( 5.1 , 5.6 )] . These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization. If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care. In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 1-770-488-7100. More information can be obtained at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm.

16 HOW SUPPLIED/STORAGE AND HANDLING 16 .1 How Supplied BOTOX (onabotulinumtoxinA) for injection is a sterile, vacuum-dried powder supplied in a single-dose vial in the following sizes: 100 Units NDC 85766-155-01 (relabeled from NDC 0023-1145-01) and NDC 85766-155-02 (relabeled from NDC 0023-1145-02) BOTOX cartons have features to alert users if contents may have been compromised. Each BOTOX vial label and carton also contains the U.S. License number: 1889 [see Dosage and Administration ( 2.1 )] . Do not use the product and contact AbbVie for additional information at 1-800-678-1605 if the labeling is not described as above. 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 )] .

16 .1 How Supplied BOTOX (onabotulinumtoxinA) for injection is a sterile, vacuum-dried powder supplied in a single-dose vial in the following sizes: 100 Units NDC 85766-155-01 (relabeled from NDC 0023-1145-01) and NDC 85766-155-02 (relabeled from NDC 0023-1145-02) BOTOX cartons have features to alert users if contents may have been compromised. Each BOTOX vial label and carton also contains the U.S. License number: 1889 [see Dosage and Administration ( 2.1 )] . Do not use the product and contact AbbVie for additional information at 1-800-678-1605 if the labeling is not described as above.