Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

BOTOX (BLA-103000)

(OnabotulinumtoxinA)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/18/2024 (SUPPL-5331)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

6.2 Postmarketing Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.1 Pregnancy

Additions and revisions underlined:

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

8.4 Geriatric Use

Newly added information:

Platysma Bands

In the two platysma bands clinical studies of BOTOX Cosmetic, 3.6% of subjects (13 subjects) treated with BOTOX Cosmetic were 65 years or older. Although the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older, clinical studies of BOTOX Cosmetic did not include sufficient numbers of subjects 65 years or older to determine whether they respond differently from younger subjects.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

BOTOX has been used at the recommended dose to treat chronic migraine, severe underarm sweating,

blepharospasm, or strabismus, or when BOTOX Cosmetic has been used at the recommended dose to treat frown lines, crow’s feet lines, forehead lines, or vertical bands connecting the jaw and neck.

BOTOX Cosmetic is a prescription medicine for adults that is injected into muscles and used for a short period of time (temporary) to improve the look of:

moderate to severe frown lines between the eyebrows (glabellar lines)
moderate to severe crow’s feet lines
moderate to severe forehead lines
moderate to severe vertical bands connecting the jaw and neck (platysma bands)

You may receive treatment for frown lines, crow’s feet lines, forehead lines, and vertical bands connecting the jaw and neck at the same time.

Do not receive BOTOX or BOTOX Cosmetic if you:

are allergic to any of the ingredients in BOTOX or BOTOX Cosmetic. See the end of this Medication Guide for a complete list of ingredients in BOTOX and BOTOX Cosmetic.
had an allergic reaction to any other botulinum toxin product such as Myobloc® (rimabotulinumtoxinB), Dysport® (abobotulinumtoxinA), Xeomin® (incobotulinumtoxinA), Jeuveau® (prabotulinumtoxinA-xvfs), Daxxify® (daxibotulinumtoxinA-lanm), or Letybo®
(letibotulinumtoxinA-wlbg). This may not be a complete list of all botulinum toxin products.
Especially tell your doctor if you:

have received any other botulinum toxin product in the last four months.

have received injections of botulinum toxin, such as Myobloc® (rimabotulinumtoxinB), Dysport® (abobotulinumtoxinA), Xeomin® (incobotulinumtoxinA), Jeuveau® (prabotulinumtoxinA-xvfs), Daxxify® (daxibotulinumtoxinA-lanm), or Letybo® (letibotulinumtoxinA-wlbg) in the past. This may not be a complete list of all botulinum toxin products.

08/11/2023 (SUPPL-5325)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

It is not known whether BOTOX is safe and effective in people younger than:

18 years of age for treatment of overactive bladder with urinary incontinence

5 years of age for the treatment of overactive bladder due to a neurologic disease

…

What are the possible side effects of BOTOX and BOTOX Cosmetic?

BOTOX and BOTOX Cosmetic can cause serious side effects. See "What is the most important information I should know about BOTOX and BOTOX Cosmetic?"

Other side effects of BOTOX and BOTOX Cosmetic include:

…

bacteria, white blood cells, and blood in the urine of children being treated for urinary incontinence.

…

08/10/2023 (SUPPL-5327)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…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.

…

09/13/2020 (SUPPL-5317)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

(Additions underlined)

…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; paresthesia; peripheral neuropathy; radiculopathy; erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption; strabismus; tinnitus; and visual disturbances.

…

10/18/2019 (SUPPL-5310)

Approved Drug Label (PDF)

5 Warnings and Precautions

Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity

Newly added information:

In pediatric patients treated for lower limb spasticity, upper respiratory tract infection was not reported with an incidence greater than placebo.

6 Adverse Reactions

Clinical Trials Experience

Newly added information:

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 21. In a double-blind, placebo-controlled trial (Study 2), 126 patients were treated with 4 Units/kg of BOTOX, and 128 patients received 8 Units/kg to a maximum dose of 300 Units of BOTOX, and were compared to 128 patients who received placebo. Patients were followed for an average of 89 days after injection.

Addition of new table, 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)

Immunogenicity

Newly added information:

In one Phase 3 study and the open-label extension study in patients with pediatric lower limb spasticity, neutralizing antibodies developed in 2 of 264 patients (0.8%) treated with BOTOX for up to 5 treatment cycles. Both patients continued to experience clinical benefit following subsequent BOTOX treatments.

8 Use in Specific Populations

Pediatric Use

Additions and/or revisions underlined:

Spasticity

Upper Limb Spasticity

Safety and effectiveness in pediatric patients below the age of 2 years have not been established

Lower Limb Spasticity, Excluding Spasticity Caused by Cerebral Palsy

Safety and effectiveness have been established in pediatric patients 2 to 17 years of age. The safety and effectiveness of BOTOX have been established by evidence from adequate and well-controlled studies of BOTOX in patients 2 to 17 years of age with lower limb spasticity. A pediatric assessment for BOTOX demonstrates that BOTOX is safe and effective in another pediatric population. However, BOTOX is not approved for such patient population due to marketing exclusivity for another botulinum toxin.

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication guide

Additions and/or revisions underlined:

BOTOX is a prescription medicine that is injected into muscles and used:

· to treat increased muscle stiffness in children 2 to 17 years of age with lower limb spasticity, excluding spasticity caused by cerebral palsy.

06/20/2019 (SUPPL-5309)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

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)

5 Warnings and Precautions

5.10 Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity

(Additions and/or revisions underlined)

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 wi th 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%).

5.11 Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity associated with a Neurologic Condition

(Additions and/or revisions underlined)

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 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

(Additions and/or revisions underlined)

BOTOX increases the incidence of urinary tract infection. 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 Patients Treated for Bladder Dysfunction

(Newly added subsection with extensive changes to table; please refer to label)

5.2 Spread of Toxin Effect

(Additions and/or revisions underlined)

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.

5.5 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders

(Additions and/or revisions underlined)

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.

5.7 Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity Associated with a Neurologic Condition

(Newly added subsection with extensive changes to table; please refer to label)

5.9 Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus

(Additions and/or revisions underlined)

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.

6 Adverse Reactions

(Additions and/or revisions underlined)

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

Spread of Toxin Effects
Serious Adverse Reactions with Unapproved Use
Hypersensitivity Reactions
Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders
Dysphagia and Breathing Difficulties
Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity associated with a Neurologic Condition
Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm
Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus
Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity
Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity associated with a Neurologic Condition
Urinary Tract Infections in Patients with Overactive Bladder
Urinary Retention in Patients Treated for Bladder Dysfunction

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

6.2 Immunogenicity

(Extensive changes; please refer to label)

6.3 Post-Marketing Experience

(Additions and/or revisions underlined)

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; hyperhidrosis; hypoacusis; hypoaesthesia; localized muscle twitching; malaise; 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. The exact relationship of these events to the botulinum toxin injection has not been established.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Data

Animal Data

… 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).

… 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.

… The developmental no-effect level for a single maternal dose in rats (16 Units/kg) is approximately 2 times the human dose of 400 Units, based on Units/kg.

8.4 Pediatric Use

(Additions and/or revisions underlined)

Bladder Dysfunction

Safety and effectiveness in patients below the age of 18 years have not been established.

Prophylaxis of Headaches in Chronic Migraine

Safety and effectiveness in patients below the age of 18 years have not been established.

In a 12-week, multicenter, double-blind, placebo-controlled clinical trial, 123 adolescent patients (ages 12 to below 18 years) with chronic migraine were randomized to receive BOTOX 74 Units, BOTOX 155 Units, or placebo, for one injection cycle. This trial did not establish the efficacy of BOTOX, compared with placebo, for the prophylaxis of headaches in adolescents with chronic migraine.

Upper Limb Spasticity

Safety and effectiveness for the treatment of upper limb spasticity 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.

Juvenile Animal Data

In a study in which juvenile rats received intramuscular injection of BOTOX (0, 8, 16, or 24 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 ferti lity 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.

Lower Limb Spasticity

Safety and effectiveness for the treatment of lower limb spasticity in pediatric patients has not been established.

Axillary Hyperhidrosis

Safety and effectiveness in patients belowthe age of 18 years have not been established.

Cervical Dystonia

Safety and effectiveness in pediatric patients belowthe age of 16 years have not been established.

Blepharospasm and Strabismus

Safety and effectiveness in pediatric patients belowthe age of 12 years have not been established.

8.5 Geriatric Use

(Extensive changes with addition of table; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive revisions; please refer to label)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient or caretaker to read the FDA-approved patient labeling (Medication Guide).

Swallowing, Speaking or Breathing Difficulties, or Other Unusual Symptoms

Advise patients or their caretaker(s) to inform their doctor or pharmacist if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing), or if any existing symptom worsens.

Ability to Operate Machinery or Vehicles

Advise patients or their caretaker(s) that if loss of strength, muscle weakness, blurred vision, dizziness, or drooping eyelids occur, they should avoid driving a car or engaging in other potentially hazardous activities.

Voiding Symptoms after Bladder Injections

After bladder injections for urinary incontinence, advise patients to contact their physician if they experience difficulties in voiding or burning sensation upon voiding.

09/12/2018 (SUPPL-5308)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Prophylaxis of Headaches in Chronic Migraine

Safety and effectiveness in patients below the age of 18 years have not been established.

Addition of the following language:

05/16/2018 (SUPPL-5306)

Approved Drug Label (PDF)

4 Contraindications

4.1 Known Hypersensitivity to Botulinum Toxin

(Additions and/or revisions underlined)

BOTOX Cosmetic is contraindicated in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation.

4.2 Infection at the Injection Site

(Additions and/or revisions underlined)

BOTOX Cosmetic is contraindicated in the presence of infection at the proposed injection site(s).

5 Warnings and Precautions

5.1 Lack of Interchangeability between Botulinum Toxin Products

(Additions and/or revisions underlined)

The potency Units of BOTOX Cosmetic 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 Cosmetic cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method.

5.10 Dry Eye in Patients Treated with BOTOX Cosmetic

(Newly revised subsection title; Additions and/or revisions underlined)

There have been reports of dry eye associated with BOTOX Cosmetic injection in or near the orbicularis oculi muscle. If symptoms of dry eye (e.g., eye irritation, photophobia, or visual changes) persist, consider referring patients to an ophthalmologist.

5.11 Spatial Disorientation, Double Vision or Past-pointing in Patients Treated for Strabismus

(Newly revised subsection title; Additions and/or revisions underlined)

Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past pointing. Covering the affected eye may alleviate these symptoms.

5.2 Spread of Toxin Effect

(Additions and/or revisions underlined)

Postmarketing safety data from BOTOX Cosmetic 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, including spasticity in children, 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 dermatologic use of BOTOX/BOTOX Cosmetic at the labeled dose of 20 Units (for glabellar lines), 24 Units (for lateral canthal lines), 40 Units (for forehead lines with glabellar lines), 44 Units (for simultaneous treatment of lateral canthal lines and glabellar lines), 64 Units (for simultaneous treatment of lateral canthal lines, glabellar lines, and forehead lines), or 100 Units (for severe primary axillary hyperhidrosis) have been reported.

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), strabismus, or chronic migraine at the labeled doses have been reported.

5.4 Hypersensivity Reactions

(Additions and/or revisions underlined)

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 Cosmetic 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 Cardiovascular System

(Newly added subsection)

There have been reports following administration of BOTOX/Botox Cosmetic of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre- existing cardiovascular disease. Use caution when administering to patients with pre-existing cardiovascular disease.

5.6 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders

(Additions and/or revisions underlined)

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 neuromuscular disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from onabotulinumtoxinA.

5.8 Pre-existing Conditions at the Injection Site

(Newly added subsection)

Caution should be used when BOTOX Cosmetic treatment is used in the presence of inflammation at the proposed injection site(s), ptosis, or when excessive weakness or atrophy is present in the targeted muscle(s).

5.9 Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm

(Additions and/or revisions underlined)

Reduced blinking from injection of botulinum toxin products in or near the orbicularis oculi muscle can lead to corneal exposure, persistent corneal epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders.

Vigorous treatment of any corneal 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.

6 Adverse Reactions

(Additions and/or revisions underlined)

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

Spread of Toxin Effects
Hypersensitivity
Dysphagia and Breathing Difficulties

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

6.2 Immunogenicity

(Additions and/or revisions underlined)

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 BOTOX Cosmetic in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Treatment with botulinum toxins may result in the formation of neutralizing antibodies that may reduce the effectiveness of subsequent treatments by inactivating biological activity of the toxin.

In three Lateral Canthal Line trials, 916 subjects (517 subjects at 24 Units and 399 subjects at 44 Units) treated with BOTOX Cosmetic had specimens analyzed for antibody formation. Among the 916 BOTOX Cosmetic treated subjects, 14 subjects (1.5%) developed binding antibodies and no subjects (0%) developed the presence of neutralizing antibodies.

The data reflect the subjects whose test results were considered positive or negative for neutralizing activity to BOTOX Cosmetic in a mouse protection assay.

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

6.3 Post-marketing Experience

(Additions and/or revisions underlined)

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.

There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin.

New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events.

The following adverse reactions by System Organ Class have been identified during post-approval use of BOTOX/BOTOX Cosmetic:

Ear and labyrinth disorders

Hypoacusis; tinnitus; vertigo

Eye disorders

Diplopia; dry eye; lagophthalmos; strabismus; visual disturbances; vision blurred

Gastrointestinal disorders

Abdominal pain; diarrhea; dry mouth; nausea; vomiting

General disorders and administration site conditions

Denervation; malaise; pyrexia

Metabolism and nutrition disorders

Anorexia

Musculoskeletal and connective tissue disorders

Localized muscle twitching/involuntary muscle contractions; muscle atrophy; myalgia

Nervous system disorders

Brachial plexopathy; dysarthria; facial palsy; hypoaesthesia; localized numbness; myasthenia gravis; paresthesia; peripheral neuropathy; radiculopathy; syncope

Respiratory, thoracic and mediastinal disorders

Aspiration pneumonia; dyspnea; respiratory depression and/or respiratory failure

Skin and subcutaneous tissue disorders

Alopecia, including madarosis; hyperhidrosis; pruritus; skin rash (including erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption)

7 Drug Interactions

(Additions and/or revisions underlined)

No formal drug interaction studies have been conducted with BOTOX Cosmetic (onabotulinumtoxinA) for injection.

7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission

(Additions and/or revisions underlined)

Co-administration of BOTOX Cosmetic 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

(Additions and/or revisions underlined)

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

7.4 Muscle Relaxants

(Additions and/or revisions underlined)

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

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

There are no studies or adequate data from postmarketing surveillance on the developmental risk associated with use of BOTOX Cosmetic in pregnant women.

In animal studies, administrations of BOTOX Cosmetic during pregnancy resulted in adverse effects on fetal growth (decreased fetal body 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 Cosmetic (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 4 times the average high human dose for glabellar lines, lateral canthal lines, and forehead lines of 64 Units on a body weight basis (Units/kg).

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 is approximately equal the average high human dose of 64 Units based on Units/kg, and the developmental no-effect dose of 0.25 Units/kg in rabbits is less than the average high human dose 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 16 times the average high human dose of 64 Units based on Units/kg.

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

There are no data on the presence of BOTOX Cosmetic in human or animal milk, the effects on the breastfed child, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BOTOX Cosmetic and any potential adverse effects on the breastfed infant from BOTOX Cosmetic or from the underlying maternal conditions.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Glabellar Lines

In the two initial glabellar lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older.

Lateral Canthal Lines

In the two lateral canthal lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older.

Forehead Lines

In the two forehead lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

See FDA-approved patient labeling (Medication Guide)

Provide a copy of the Medication Guide and review the contents with the patient.

Swallowing, Speaking or Breathing Difficulties, or Other Unusual Symptoms

Patients should be advised to inform their doctor or pharmacist if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing), or if any existing symptom worsens.

Ability to Operate Machinery or Vehicles

Patients should be counseled that if loss of strength, muscle weakness, blurred vision, or drooping eyelids occur, they should avoid driving a car or engaging in other potentially hazardous activities.

Ophthalmic Adverse Reactions

Inform patients that Botox Cosmetic injection may cause eye dryness. Advise patients to report symptoms of eye dryness (e.g., eye pain, eye irritation, photosensitivity, or changes in vision) to their doctor.

05/15/2018 (SUPPL-5307)

Approved Drug Label (PDF)

4 Contraindications

4.3 Urinary Tract Infection or Urinary Retention

(new subsection added)

Intradetrusor injection of BOTOX is contraindicated in patients with overactive bladder or detrusor overactivity associated with a neurologic condition who have a urinary tract infection. Intradetrusor injection of BOTOX is also contraindicated in patients with urinary retention and in patients with post-void residual (PVR) urine volume >200 mL, who are not routinely performing clean intermittent self-catheterization (CIC).

5 Warnings and Precautions

5.10 Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity

(new subsection added)

Bronchitis was reported more as an adverse reaction in patients treated for upper limb spasticity with BOTOX (3% at 251 Units-360 Units total dose), compared to placebo (1%). In 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 event in patients treated with BOTOX (2% at 300 Units to 400 Units total dose) compared to placebo (1%).

5.11 Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity associated with a Neurologic Condition

(new subsection added)

5.12 Urinary Tract Infections in Patients with Overactive Bladder

(new subsection added)

5.13 Urinary Retention in Patients Treated for Bladder Dysfunction

(new subsection added)

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 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 7. The duration of post- injection catheterization for those who developed urinary retention is also shown.

Table 7: Proportion of Patients Catheterizing for Urinary Retention and Duration of Catheterization Following an Injection in Double-blind, Placebo-controlled Clinical Trials in OAB

(please refer to label to view Table 7)

Patients with diabetes mellitus treated with BOTOX were more likely to develop urinary retention than those without diabetes, as shown in Table 8.

Table 8: Proportion of Patients Experiencing Urinary Retention Following an Injection in Double-blind, Placebo-controlled Clinical Trials in OAB According to History of Diabetes Mellitus

(please refer to label to view Table 8)

Detrusor Overactivity associated with a Neurologic Condition

In two double-blind, placebo-controlled trials in 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 9. The duration of post-injection catheterization for those who developed urinary retention is also shown.

Table 9: Proportion of 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

(please refer to label to view Table 9)

Among 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 10).

Table 10: Proportion of 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

(please refer to label to view Table 10)

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.

5.2 Spread of Toxin Effect

(subsection revised, additions underlined)

…

5.5 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders

(additions underlined)

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.

5.7 Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity associated with a Neurologic Condition

(new subsection added)

Patients with compromised respiratory status treated with BOTOX for spasticity should be monitored closely. In a double-blind,

placebo-controlled, parallel group study in patients treated for upper limb spasticity with stable reduced pulmonary function (defined as FEV1 40-80% of predicted value and FEV1/FVC less than or equal to 0.75), the event rate in change of Forced Vital Capacity (FVC) greater than or equal to15% or greater than or equal to 20% was generally greater in patients treated with BOTOX than in patients treated with placebo (see Table 5).

Table 5: Event Rate Per Patient Treatment Cycle Among 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

(please refer to label to view Table 5)

In 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.

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 greater than or equal to15% or greater than or equal to 20% was generally greater in patients treated with BOTOX than in patients treated with placebo (see Table 6).

Table 6: 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

(please refer to label to view Table 6)

5.9 Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus

(new subsection added)

Inducing paralysisDuring 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions, please refer to label)

6.2 Immunogenicity

(additions underlined)

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to onabotulinumtoxinA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a long term, open-label study evaluating 326 cervical dystonia patients treated for an average of 9 treatment sessions with the current formulation of BOTOX4 (1.2%) patients had positive antibody tests. All 4 of these patients responded to BOTOX therapy at the time of the positive antibody test. However, 3 of these patients developed clinical resistance after subsequent treatment, while the fourth patient continued to respond to BOTOX therapy for the remainder of the study.

One patient among the 445 hyperhidrosis patients (0.2%), two patients among the 380 adult upper limb spasticity patients (0.5%) and no patients among 406 migraine patients with analyzed specimens developed the presence of neutralizing antibodies.

In overactive bladder patients with analyzed specimens from the two phase 3 studies and the open-label extension study, neutralizing antibodies developed in 0 of 954 patients (0.0%) while receiving BOTOX 100 Unit doses and 3 of 260 patients (1.2%) after subsequently receiving at least one 150 Unit dose. Response to subsequent BOTOX treatment was not different following seroconversion in these three patients.

In detrusor overactivity associated with neurologic condition patients with analyzed specimens in the drug development program (including the open-label extension study), neutralizing antibodies developed in 3 of 300 patients (1.0%) after receiving only BOTOX 200 Unit doses and 5 of 258 patients (1.9%) after receiving at least one 300 Unit dose. Following development of neutralizing antibodies in these 8 patients, 4 continued to experience clinical benefit, 2 did not experience clinical benefit, and the effect on the response to BOTOX in the remaining 2 patients is not known.

The data reflect the patients whose test results were considered positive for neutralizing activity to BOTOX in a mouse protection assay or negative based on a screening ELISA assay or mouse protection assay.

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

6.3 Post-Marketing Experience

(additions underlined)

There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin.

(additions underlined)

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

Spread of Toxin Effects
Serious Adverse Reactions with Unapproved Use
Hypersensitivity Reactions
Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders
Dysphagia and Breathing Difficulties
Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity associated with a Neurologic Condition
Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm
Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus
Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity
Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity associated with a Neurologic Condition
Urinary Tract Infections in Patients with Overactive Bladder
Urinary Retention in Patients Treated for Bladder Dysfunction

8 Use in Specific Populations

8.1 Pregnancy

(additions and revisions underlined)

Risk Summary

There are no studies or adequate data from postmarketing surveillance on the developmental risk associated with use of BOTOX in pregnant women. In animal studies, administration of BOTOX during pregnancy resulted in adverse effects on fetal growth (decreased fetal weight and skeletal ossification) at clinically relevant doses, which were associated with maternal toxicity [see Data)].

Data

Animal Data

When BOTOX (4, 8, or 16 Units/kg) was administered intramuscularly to pregnant mice or rats two times during the period of organogenesis (on gestation days 5 and 13), reductions in fetal body weight and decreased fetal skeletal ossification were observed at the two highest doses. The no-effect dose for developmental toxicity in these studies (4 Units/kg) is approximately equal to the human dose of 400 Units, on a body weight basis (Units/kg).

When BOTOX was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or 0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the two highest doses in rats and at the highest dose in rabbits. These doses were also associated with significant maternal toxicity, including abortions, early deliveries, and maternal death. The developmental no- effect doses in these studies of 1 Unit/kg in rats and 0.25 Units/kg in rabbits are less than the human dose of 400 Units, based on Units/kg.

When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three different periods of development (prior to implantation, implantation, or organogenesis), no adverse effects on fetal development were observed. The developmental no-effect level for a single maternal dose in rats (16 Units/kg) is approximately 2 times the human dose of 400 Units, based on Units/kg.

8.4 Pediatric Use

(additions underlined)

Bladder Dysfunction

Safety and effectiveness in patients below the age of 18 years have not been established.

Prophylaxis of Headaches in Chronic Migraine

Safety and effectiveness in patients below the of 18 years have not been established.

Spasticity

Safety and effectiveness in patients below the age of 18 years have not been established.

Axillary Hyperhidrosis

Safety and effectiveness in patients below the age of 18 years have not been established.

Cervical Dystonia

Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

Blepharospasm and Strabismus

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

8.5 Geriatric Use

(subsection revised, additions underlined)

Of the 2145 patients in placebo-controlled clinical studies of BOTOX for the treatment of spasticity, 33.5% were 65 or older, and 7.7% were 75 years of age or older. No overall differences in safety were observed between elderly patients and younger patients.

In clinical studies of BOTOX across other indications, no overall differences in safety were observed between elderly patients and younger patients, with the exception of Overactive Bladder (see below). Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Overactive Bladder

Of 1242 overactive bladder patients in placebo-controlled clinical studies of BOTOX, 41.4% were 65 years of age or older, and 14.7% were 75 years of age or older. Adverse reactions of UTI and urinary retention were more common in patients 65 years of age or older in both placebo and BOTOX groups compared to younger patients (see Table 18). Otherwise, there were no overall differences in the safety profile following BOTOX treatment between patients aged 65 years and older compared to younger patients in these studies.

Table 18: Incidence of Urinary Tract Infection and Urinary Retention according to Age Group during First Placebo- controlled Treatment, Placebo-controlled Clinical Trials in Patients with OAB

(please refer to label to view Table 18)

Observed effectiveness was comparable between these age groups in placebo-controlled clinical studies.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Voiding Symptoms after Bladder Injections

After bladder injections for urinary incontinence, advise patients to contact their physician if they experience difficulties in voiding or burning sensation upon voiding.

…

10/02/2017 (SUPPL-5303)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Spread of Toxin Effect

5.6 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders Revised heading

5.11 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

In Tables 2 and 3, Subjects replace Patients.

Following Table 3, newly added information below:

Forehead Lines

Table 4 lists selected adverse reactions reported by greater than or equal to 1% of BOTOX Cosmetic treated subjects (N equals 665) aged 18 to 77 who were evaluated in two randomized, double-blind, placebo-controlled clinical studies to assess the use of BOTOX Cosmetic in the improvement of the appearance of forehead lines with glabellar lines.

Table 4: Adverse Reactions Reported by greater than or equal to 1% of BOTOX Cosmetic treated Subjects and More Frequent than in Placebo- treated Subjects, in Double-blind, Placebo-controlled Clinical Studies of Treatment of Forehead Lines

Newly added table; please refer to label for complete information.

There were no additional adverse drug reactions reported with the simultaneous treatment of forehead lines, glabellar lines, and lateral canthal lines.

6.2 Immunogenicity

Additions and/or revisions underlined:

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion, revised as below:

Risk Summary

There are no studies or adequate data from postmarketing surveillance on the developmental risk associated with use of BOTOX Cosmetic in pregnant women.

Data

Animal Data

When BOTOX Cosmetic was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or 0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the two highest doses in rats and at the highest dose in rabbits. These doses were also associated with significant maternal toxicity, including abortions, early deliveries, and maternal death. The developmental no-effect doses in these studies of 1 Unit/kg in rats is approximately equal the average high human dose of 64 Units based on Units/kg, and the developmental no-effect dose of 0.25 Units/kg in rabbits is less than the average high human dose based on Units/kg.

8.2 Lactation

PLLR conversion; revised as below:

Risk Summary

There are no data on the presence of BOTOX Cosmetic in human or animal milk, the effects on the breastfed child, or the effects on milk production.

8.5 Geriatric Use

Newly Added information following Lateral Canthal Lines:

Forehead Lines

In the two forehead lines clinical studies of BOTOX Cosmetic, the responder rates appeared to be higher for subjects younger than age 65 than for subjects 65 years or older.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

BOTOX Cosmetic is a prescription medicine for adults that is injected into muscles and used for a short period of time (temporary) to improve the look of:

moderate to severe crow’s feet lines
moderate to severe forehead lines
You may receive treatment for frown lines, crow’s feet lines, and forehead lines at the same time.
It is not known if BOTOX Cosmetic is safe and effective for use more than 1 time every 3 months.
What are the possible side effects of BOTOX and BOTOX Cosmetic?
BOTOX and BOTOX Cosmetic can cause serious side effects. See "What is the most important information I should know about BOTOX and BOTOX Cosmetic?"
Other side effects of BOTOX and BOTOX Cosmetic include:

drooping eyebrows

04/20/2017 (SUPPL-5302)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Human Albumin and Transmission of Viral Diseases

(Additions and/or revisions are underlined)

5.5 Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders

(Additions and/or revisions are underlined)

…Patients with known or unrecognized neuromuscular disorders or neuromuscular 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

…

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…

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

In clinical studies of BOTOX across other indications, no overall differences in safety were observed between elderly patients and younger patients, with the exception of Overactive Bladder (see below). Other reported clinical experience has not identified differences in responses between the elderly and younger patients do, but greater sensitivity of some older individuals cannot be ruled out.

04/04/2017 (SUPPL-5296)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.13 Urinary Retention in Patients Treated for Bladder Dysfunction

(additions underlined)

…

A placebo-controlled, double-blind post-approval 52 week study with BOTOX 100 Units (Study NDO-3) was conducted in non- catheterizing 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Table 14 presents the most frequently reported adverse reactions in a placebo-controlled, double-blind post-approval 52 week study with BOTOX 100 Units (Study NDO-3) conducted in MS patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition. These patients were not adequately managed with at least one anticholinergic agent and not catheterized at baseline. The table below presents the most frequently reported adverse reactions within 12 weeks of injection.

(please refer to Table 14 in label)

The following adverse events with BOTOX 100 Units were reported at any time following initial injection and prior to re-injection or study exit (median duration of exposure was 51 weeks): urinary tract infections (39%), bacteriuria (18%), urinary retention (17%), residual urine volume* (17%), dysuria (9%), and hematuria (5%).

No difference in the MS exacerbation annualized rate (i.e., number of MS exacerbating events per patient-year) was observed (BOTOX =0, placebo =0.07).

04/04/2017 (SUPPL-5297)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

(additions underlined)

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 antibo dy) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to onabotulinumtoxinA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a long term, open-label study evaluating 326 cervical dystonia patients treated for an average of 9 treatment sessions with the current formulation of BOTOX, 4 (1.2%) patients had positive antibody tests. All 4 of these patients responded to BOTOX therapy at the time of the positive antibody test. However, 3 of these patients developed clinical resistance after subsequent treatment, while the fourth patient continued to respond to BOTOX therapy for the remainder of the study.

One patient among the 445 hyperhidrosis patients (0.2%), two patients among the 380 adult upper limb spasticity patients (0.5 %) and no patients among 406 migraine patients with analyzed specimens developed the presence of neutralizing antibodies.

…

04/04/2017 (SUPPL-5298)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

(additions underlined)

…

01/21/2016 (SUPPL-5252)

Approved Drug Label (PDF)

5 Warnings and Precautions

Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity

Bronchitis was reported more frequently as an adverse reaction in patients treated for upper limb spasticity with Botox (3% at 251 Units-360 Units total dose), compared to placebo (1%). In 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 event in patients treated with Botox (2% at 300 Units to 400 Units total dose) compared to placebo (1%).