Botox Drug Information

Units into each of 3 sites per affected eye Strabismus

The dose is based on prism diopter correction or previous response to treatment with BOTOX 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. 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.

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. 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. 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, 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. 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 ), but no sooner than 12 weeks from the prior bladder 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.

Use immediately after reconstitution in the syringe. 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.

After the injections are given, the saline used for bladder wall visualization should be drained. 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 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. 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, may be administered prior to treatment administration on the day of treatment.

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.

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). 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 *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.

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 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 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. Additional general adult spasticity dosing information is also applicable to pediatric spasticity patients. 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 7: BOTOX Dosing by 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.

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.

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.

The hyperhidrotic area to be injected should be defined using standard staining techniques, e.g., Minor’s Iodine-Starch Test. 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. 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 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.

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.

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 *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 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. 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. 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. 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 Elevated PVR not requiring catheterization. No difference in the MS exacerbation annualized rate (i.e., number of MS exacerbating events per patient-year) was observed (BOTOX =0, placebo =0.07).

Pediatric Detrusor Overactivity associated with a Neurologic Condition Table 18 presents the most frequently reported adverse reactions in Study 191622-120, a double-blind, parallel-group study conducted in pediatric patients with detrusor overactivity associated with a neurologic condition. The table below presents the most frequently reported adverse reactions during the 12 weeks following intradetrusor administration of BOTOX 200 Units. Table 18: Adverse Reactions Reported by ≥ 3% of BOTOX Treated Pediatric Patients within the First 12 Weeks after Intradetrusor Injection, Study 191622- No change was observed in the overall safety profile with repeat dosing.

The most common adverse reactions in patients who received BOTOX 6 U/kg and less than a total dose of 200 U in Study 191622-120 were urinary tract infection (UTI), bacteriuria and hematuria. Discontinuations due to an adverse event were 4% in the BOTOX group and 1% in the placebo group. The most frequent adverse events leading to discontinuation in the BOTOX group were neck pain, headache, worsening migraine, muscular weakness and eyelid ptosis.

The most frequently reported adverse reactions following injection of BOTOX for chronic migraine appear in Table 19. Table 19: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Two Chronic Migraine Double-Blind, Placebo-Controlled Clinical Trials 2 1 Other adverse reactions that occurred more frequently in the BOTOX group compared to the placebo group at a frequency less than 1% and potentially BOTOX related include: vertigo, dry eye, eyelid edema, dysphagia, eye infection, and jaw pain. Adult Upper Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX for adult upper limb spasticity appear in Table 20.

Table 20: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Adult Upper Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trials Twenty-two adult patients, enrolled in double-blind placebo controlled studies, received 400 Units or higher of BOTOX for treatment of upper limb spasticity. In addition, 44 adults received 400 Units of BOTOX or higher for four consecutive treatments over approximately one year for treatment of upper limb spasticity. The type and frequency of adverse reactions observed in patients treated with 400 Units of BOTOX were similar to those reported in patients treated for upper limb spasticity with 360 Units of BOTOX.

Patients were followed for an average of 91 days after injection. Table 22: Adverse Reactions Reported by ≥2% of BOTOX 6 Units/kg Treated Patients and More Frequent than in Placebo-Treated Patients in Pediatric Upper Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 1) Includes upper respiratory tract infection and viral upper respiratory tract infection Includes seizure and partial seizure Pediatric Lower Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX in pediatric patients 2 to 17 years of age with lower limb spasticity appear in Table 23. Table 23: Adverse Reactions Reported by ≥2% of BOTOX 8 Units/kg Treated Patients and More Frequent than in Placebo-Treated Patients in Pediatric Lower Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 2) Cervical Dystonia In cervical dystonia patients evaluated for safety in double-blind and open-label studies following injection of BOTOX, the most frequently reported adverse reactions were dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%).

Other events reported in 2-10% of patients in any one study in decreasing order of incidence include: increased cough, flu syndrome, back pain, rhinitis, dizziness, hypertonia, soreness at injection site, asthenia, oral dryness, speech disorder, fever, nausea, and drowsiness. Stiffness, numbness, diplopia, ptosis, and dyspnea have been reported. Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of BOTOX resulting from the spread of the toxin outside the injected muscles.

The most common severe adverse reaction associated with the use of BOTOX injection in patients with cervical dystonia is dysphagia with about 20% of these cases also reporting dyspnea. Most dysphagia is reported as mild or moderate in severity. However, it may be associated with more severe signs and symptoms.

Additionally, reports in the literature include a case of a female patient who developed brachial plexopathy two days after injection of 120 Units of BOTOX for the treatment of cervical dystonia, and reports of dysphonia in patients who have been treated for cervical dystonia. Primary Axillary Hyperhidrosis The most frequently reported adverse reactions (3-10% of adult patients) following injection of BOTOX in double-blind studies included injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety. Other events reported in prior clinical studies in decreasing order of incidence include: irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia, entropion, diffuse skin rash, and local swelling of the eyelid skin lasting for several days following eyelid injection.

In two cases of VII nerve disorder, reduced blinking from BOTOX injection of the orbicularis muscle led to serious corneal exposure, persistent epithelial defect, corneal ulceration and a case of corneal perforation. Focal facial paralysis, syncope, and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm. Strabismus Extraocular muscles adjacent to the injection site can be affected, causing vertical deviation, especially with higher doses of BOTOX.

The incidence rates of these adverse effects in 2058 adults who received a total of 3650 injections for horizontal strabismus was 17%. The incidence of ptosis has been reported to be dependent on the location of the injected muscles, 1% after inferior rectus injections, 16% after horizontal rectus injections and 38% after superior rectus injections. In a series of 5587 injections, retrobulbar hemorrhage occurred in 0.3% of cases.

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies to onabotulinumtoxinA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. All 4 of these patients responded to BOTOX therapy at the time of the positive antibody test. However, 3 of these patients developed clinical resistance after subsequent treatment, while the fourth patient continued to respond to BOTOX therapy for the remainder of the study.

Both patients continued to experience clinical benefit following subsequent BOTOX treatments. Response to subsequent BOTOX treatment was not different following seroconversion in these three patients. Following development of neutralizing antibodies in these 8 patients, 4 continued to experience clinical benefit, 2 did not experience clinical benefit, and the effect on the response to BOTOX in the remaining 2 patients is not known.

In 99 pediatric patients who had a negative baseline result for binding antibodies or neutralizing antibodies and had at least one evaluable post-baseline value from one randomized double-blind study and one double-blind extension study, no patients developed neutralizing antibodies after receiving 50 Units to 200 Units of BOTOX. The data reflect the patients whose test results were considered positive for neutralizing activity to BOTOX in a mouse protection assay or negative based on a screening ELISA assay or mouse protection assay. Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin.

The critical factors for neutralizing antibody formation have not been well characterized. The results from some studies suggest that BOTOX injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of BOTOX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: abdominal pain; alopecia, including madarosis; anorexia; brachial plexopathy; denervation/muscle atrophy; diarrhea; dry eye; eyelid edema (following periocular injection); hyperhidrosis; hypoacusis; hypoaesthesia; localized muscle twitching; malaise; Mephisto sign; paresthesia; peripheral neuropathy; radiculopathy; erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption; strabismus; tinnitus; and visual disturbances.

There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin. There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease.

The exact relationship of these events to the botulinum toxin injection has not been established. New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events.

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.

Anticholinergic Drugs Use of anticholinergic drugs after administration of BOTOX may potentiate systemic anticholinergic effects.

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.

Muscle Relaxants

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of BOTOX.

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. 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 Units/kg or rabbits 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.

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). The most common adverse reactions in this population were urinary tract infection, bacteriuria, hematuria, and leukocyturia.

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 to evaluate the efficacy and safety of BOTOX in pediatric patients aged 12 to 17 years with overactive bladder.

Fifty-five patients who had an inadequate response to or were intolerant of at least one anticholinergic medication were treated with BOTOX. There was not a statistically significant difference in the mean change from baseline in the daily average frequency of daytime urinary incontinence episodes (primary efficacy endpoint) at week 12 post-treatment when a medium and high dose were each compared to a low dose of BOTOX. The adverse reactions in pediatric patients treated with BOTOX were comparable with the known safety profile in adults with overactive bladder.

Prophylaxis of Headaches in Chronic Migraine Safety and effectiveness in patients below the age of 18 years have not been established. This trial did not establish the efficacy of BOTOX, compared with placebo, for the prophylaxis of headaches in adolescents with chronic migraine. Spasticity Safety and effectiveness have been established in pediatric patients 2 to 17 years of age.

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Axillary Hyperhidrosis Safety and effectiveness in patients below the age of 18 years have not been established. Juvenile Animal Data In a study in which juvenile rats received intramuscular injection of BOTOX Units/kg every other week from postnatal day 21 for 12 weeks, changes in bone size/geometry associated with decreased bone density and bone mass were observed at all doses, in association with limb disuse, decreased muscle contraction, and decreased body weight gain.

Impairment of fertility and male reproductive organ histopathology (degeneration of seminiferous tubules of the testis) were observed at the mid and high doses. Bone and male reproductive organ effects showed evidence of reversibility after dosing cessation. The no-effect dose for adverse developmental effects in juvenile animals (8 Units/kg) is similar to the human dose (400 Units) on a body weight (kg) basis.

• BOTOX is contraindicated: In patients who are hypersensitive to any botulinum toxin product or to any of the components in the formulation. 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). Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation Infection at the proposed injection site Intradetrusor Injections: Urinary tract infection or urinary retention

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.

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.