Botox Injection, Powder, Lyophilized, For Solution

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.

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.

The following adverse reactions to BOTOX (onabotulinumtoxinA) for injection are discussed in greater detail in other sections of the labeling:

1. Spread of Toxin Effects [see Warnings and Precautions ( 5.1 )]
   
2. Serious Adverse Reactions with Unapproved Use [see Warnings and Precautions ( 5.3 )]
   
3. Hypersensitivity Reactions [see Contraindications ( 4 ) a nd Warnings and Precautions ( 5.4 )]
   
4. Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders [see Warnings and Precautions ( 5.5 )]
   
5. Dysphagia and Breathing Difficulties [see Warnings and Precautions ( 5.6 )]
   
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 )]
   
7. Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm [see Warnings and Precautions ( 5.8 )]
   
8. Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus [see Warnings and Precautions ( 5.9 )]
   
9. Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity [se e Warnings and Precautions ( 5.10 )]
   
10. Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity Associated with a Neurologic Condition [see Warnings and Precautions ( 5.11 )]
    
11. Urinary Tract Infections in Patients with Overactive Bladder [see Warnings and Precautions ( 5.12 )]
    
12. Urinary Retention in Patients Treated for Bladder Dysfunction [see Warnings and Precautions ( 5.13 )]

• 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 FEV1 40-80% of predicted value and FEV1/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 Experienced at Least a 15% or 20% Decrease in FVC From Baseline at Week 1, 6, 12 Post-injection with Up to Two Treatment Cycles with BOTOX or Placebo

BOTOX

360 Units

BOTOX

240 Units

Placebo

≥15%

≥20%

≥15%

≥20%

≥15%

≥20%

Week 1

4%

0%

3%

0%

7%

3%

Week 6

7%

4%

4%

2%

2%

2%

Week 12

10%

5%

2%

1%

4%

1%

Differences from placebo were not statistically significant

In adult spasticity patients with reduced lung function, upper respiratory tract infections were also reported more frequently as adverse reactions in patients treated with BOTOX than in patients treated with placebo

[se

e Warnings and Precautions (5.10)].

In a double-blind, placebo-controlled, parallel group study in adult patients with detrusor overactivity associated with a neurologic condition and restrictive lung disease of neuromuscular etiology [defined as FVC 50-80% of predicted value in patients with spinal cord injury between C5 and C8, or MS] the event rate in change of Forced Vital Capacity ≥15% or ≥20% was generally greater in patients treated with BOTOX than in patients treated with placebo (see Table 9).

Table 9: Number and Percent of Patients Experiencing at Least a 15% or 20% Decrease in FVC From Baseline at Week 2, 6, 12 Post-Injection with BOTOX or Placebo

BOTOX

200 Units

Placebo

≥15%

≥20%

≥15%

≥20%

Week 2

0/15 (0%)

0/15 (0%)

1/11 (9%)

0/11 (0%)

Week 6

2/13 (15%)

1/13 (8%)

0/12 (0%)

0/12 (0%)

Week 12

0/12(0%)

0/12 (0%)

0/7 (0%)

0/7 (0%) 5.8

Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm

Reduced blinking from BOTOX injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. 5.9

Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus

During the administration of BOTOX for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred. It is recommended that appropriate instruments to decompress the orbit be accessible. 5.10

Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity

Bronchitis was reported more frequently as an adverse reaction in adult patients treated for upper limb spasticity with BOTOX (3% at 251 Units-360 Units total dose), compared to placebo (1%). In adult patients with reduced lung function treated for upper limb spasticity, upper respiratory tract infections were also reported more frequently as adverse reactions in patients treated with BOTOX (11% at 360 Units total dose; 8% at 240 Units total dose) compared to placebo (6%). In adult patients treated for lower limb spasticity, upper respiratory tract infections were reported more frequently as an adverse reaction in patients treated with BOTOX (2% at 300 Units to 400 Units total dose) compared to placebo (1%). In pediatric patients treated for upper limb spasticity, upper respiratory tract infections were reported more frequently as an adverse reaction in patients treated with BOTOX (17% at 6 Units/kg and 10% at 3 Units/kg) compared to placebo (9%). In pediatric patients treated for lower limb spasticity, upper respiratory tract infection was not reported with an incidence greater than placebo. 5.11

Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity

Associated

with a Neurologic Condition

Autonomic dysreflexia associated with intradetrusor injections of BOTOX could occur in patients treated for detrusor overactivity associated with a neurologic condition and may require prompt medical therapy. In clinical trials, the incidence of autonomic dysreflexia was greater in adult patients treated with BOTOX 200 Units compared with placebo (1.5% versus 0.4%, respectively). 5.12

Urinary Tract Infections in Patients with Overactive Bladder

BOTOX increases the incidence of urinary tract infection [see Adverse Reactions (6.1)]. Clinical trials for overactive bladder excluded patients with more than 2 UTIs in the past 6 months and those taking antibiotics chronically due to recurrent UTIs. Use of BOTOX for the treatment of overactive bladder in such patients and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is likely to outweigh the potential risk. 5.13

Urinary Retention in

Adults

Treated for Bladder Dysfunction

Due to the risk of urinary retention, treat only patients who are willing and able to initiate catheterization post-treatment, if required, for urinary retention.

In patients who are not catheterizing, post-void residual (PVR) urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks, particularly in patients with multiple sclerosis or diabetes mellitus. Depending on patient symptoms, institute catheterization if PVR urine volume exceeds 200 mL and continue until PVR falls below 200 mL. Instruct patients to contact their physician if they experience difficulty in voiding as catheterization may be required.

The incidence and duration of urinary retention is described below for adult patients with overactive bladder and detrusor overactivity associated with a neurologic condition who received BOTOX or placebo injections.

Overactive Bladder

In double-blind, placebo-controlled trials in patients with OAB, the proportion of subjects who initiated clean intermittent catheterization (CIC) for urinary retention following treatment with BOTOX or placebo is shown in Table 10. The duration of post-injection catheterization for those who developed urinary retention is also shown.

Table 10: Proportion of Patients Catheterizing for Urinary Retention and Duration of Catheterization Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials in OAB

Timepoint

BOTOX 100 Units

(N=552)

Placebo

(N=542)

Proportion of Patients Catheterizing for Urinary Retention

At any time during complete treatment cycle

6.5% (n=36)

0.4% (n=2)

Duration of Catheterization for Urinary Retention (Days)

Median

63

11

Min, Max

1, 214

3, 18

Patients with diabetes mellitus treated with BOTOX were more likely to develop urinary retention than those without diabetes, as shown in Table 11.

Table 11: Proportion of Patients Experiencing Urinary Retention Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials in OAB According to History of Diabetes Mellitus

Patients with

Diabet

e

s

Patients without D

iabet

e

s

BOTOX 100 Units

(N=81)

Placebo

(N=69)

BOTOX 100 Units (N=526)

Placebo

(N=516)

Urinary retention

12.3% (n=10)

0

6.3% (n=33)

0.6% (n=3)

Adult

Detrusor Overactivity associated with a Neurologic Condition

In two double-blind, placebo-controlled trials in adult patients with detrusor overactivity associated with a neurologic condition (NDO-1 and NDO-2), the proportion of subjects who were not using clean intermittent catheterization (CIC) prior to injection and who subsequently required catheterization for urinary retention following treatment with BOTOX 200 Units or placebo is shown in Table 12. The duration of post-injection catheterization for those who developed urinary retention is also shown.

Table 12: Proportion of Adult Patients Not Using CIC at Baseline and then Catheterizing for Urinary Retention and Duration of Catheterization Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials

Timepoint

BOTOX 200 Units

(N=108)

Placebo

(N=104)

Proportion of Patients Catheterizing for Urinary Retention

At any time during complete treatment cycle

30.6% (n=33)

6.7% (n=7)

Duration of Catheterization for Urinary Retention (Days)

Median

289

358

Min, Max

1, 530

2, 379

Among adult patients not using CIC at baseline, those with Multiple Sclerosis (MS) were more likely to require CIC post-injection than those with Spinal Cord Injury (SCI) (see Table 13).

Table 13: Proportion of Adult Patients by Etiology (MS and SCI) Not Using CIC at Baseline and then Catheterizing for Urinary Retention Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials

Timepoint

MS

SCI

BOTOX 200 Units

(N=86)

Placebo

(N=88)

BOTOX 200 Units

(N=22)

Placebo

(N=16)

At any time during complete treatment cycle

31% (n=27)

5% (n=4)

27% (n=6)

19% (n=3)

A placebo-controlled, double-blind post-approval 52 week study with BOTOX 100 Units (Study NDO-3) was conducted in non-catheterizing adult MS patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition. Catheterization for urinary retention was initiated in 15.2% (10/66) of patients following treatment with BOTOX 100 Units versus 2.6% (2/78) on placebo at any time during the complete treatment cycle. The median duration of post-injection catheterization for those who developed urinary retention was 64 days for BOTOX 100 Units and 2 days for placebo. 5.14

Human Albumin and Transmission of Viral Diseases

This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.

• 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 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. 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 ) Frontalisb 20 Units divided in 4 sites Corrugatorb 10 Units divided in 2 sites Procerus 5 Units in 1 site Occipitalisb 30 Units divided in 6 sites Temporalisb 40 Units divided in 8 sites Trapeziusb 30 Units divided in 6 sites Cervical Paraspinal Muscle Groupb 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 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 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 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. 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).

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.

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.