IMPORTANT SAFETY INFORMATION (continued)
CONTRAINDICATIONS
BOTOX® is contraindicated in the presence of infection at the proposed injection site(s)
and in individuals with known hypersensitivity to any botulinum toxin preparation or to
any of the components in the formulation.
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 (UTI). 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).
WARNINGS AND PRECAUTIONS
Lack of Interchangeability Between Botulinum Toxin Products
The potency Units of BOTOX® are specific to the preparation and assay method
utilized. They are not interchangeable with other preparations of botulinum toxin
products and, therefore, Units of biological activity of BOTOX® cannot be compared to nor
converted into Units of any other botulinum toxin products assessed with any other specific assay method.
Spread of Toxin Effect
See Boxed Warning.
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.
Serious Adverse Reactions With Unapproved Use
Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with
some adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX®
injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant
spread of toxin, but may have resulted from the administration of BOTOX® to the site of injection and/or
adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant disabilities.
There is insufficient information to identify factors associated with an increased risk for adverse reactions
associated with the unapproved uses of BOTOX®. The safety and effectiveness of BOTOX® for unapproved uses
have not been established.
Hypersensitivity Reactions
Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness,
urticaria, soft-tissue edema, and dyspnea. If such a reaction occurs, further injection of BOTOX® should be discontinued
and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine
was used as the diluent, and consequently the causal agent cannot be reliably determined.
Increased Risk of Clinically Significant Effects With Pre-existing Neuromuscular Disorders
Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis (ALS), or neuromuscular
junction disorders (eg, myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given botulinum
toxin. Patients with known or unrecognized neuromuscular disorders or neuromuscular junction disorders may be
at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis,
dysphonia, dysarthria, severe dysphagia, and respiratory compromise from therapeutic doses of BOTOX® (see Warnings and Precautions).
Dysphagia and Breathing Difficulties
Treatment with BOTOX® and other botulinum toxin products can result in swallowing or breathing difficulties.
Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications.
In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in
breathing or oropharyngeal muscles that control swallowing or breathing (see Boxed Warning).
Pulmonary Effects of BOTOX® in Patients With Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity Associated With a Neurologic Condition
Patients with compromised respiratory status treated with BOTOX® for
spasticity or detrusor overactivity associated with a neurologic condition should be
monitored closely.
Corneal Exposure and Ulceration in Patients Treated With BOTOX® for Blepharospasm
Reduced blinking from BOTOX® injection of the orbicularis muscle can lead to corneal
exposure, persistent epithelial defect, and corneal ulceration, especially in patients with
VII nerve disorders.
Retrobulbar Hemorrhages in Patients Treated With BOTOX® for Strabismus
During the administration of BOTOX® for the treatment of strabismus, retrobulbar
hemorrhages sufficient to compromise retinal circulation have occurred. It is
recommended that appropriate instruments to decompress the orbit be accessible.
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 to 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%).
Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity Associated With a Neurologic Condition
Autonomic dysreflexia associated with intradetrusor injections of BOTOX® could occur
in patients treated for detrusor overactivity associated with a neurologic condition and
may require prompt medical therapy. In clinical trials, the incidence of autonomic
dysreflexia was greater in patients treated with BOTOX® 200 Units compared with
placebo (1.5% versus 0.4%, respectively).
Urinary Tract Infections in Patients With Overactive Bladder
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.
Urinary Retention in Patients Treated for Bladder Dysfunction
Due to the risk of urinary retention, treat only patients who are willing and able to initiate
catheterization post-treatment, if required, for urinary retention.
In patients who are not catheterizing, post-void residual (PVR) urine volume should be
assessed within 2 weeks post treatment and periodically as medically appropriate up to
12 weeks, particularly in patients with multiple sclerosis or diabetes mellitus. Depending
on patient symptoms, institute catheterization if PVR urine volume exceeds 200 mL and
continue until PVR falls below 200 mL. Instruct patients to contact their physician if they
experience difficulty in voiding as catheterization may be required.
Overactive Bladder
In clinical trials, 6.5% of patients (36/552) initiated clean intermittent catheterization for
urinary retention following treatment with BOTOX® 100 Units as compared to 0.4% of
patients (2/542) treated with placebo. The median duration of catheterization for patients treated with BOTOX®
100 Units was 63 days (minimum 1 day to maximum 214 days) as compared to a median duration 11 days (minimum 3 days to maximum
18 days) for patients receiving placebo.
Patients with diabetes mellitus treated with BOTOX® were more likely to develop urinary
retention than nondiabetics. In clinical trials, 12.3% of patients (10/81) with diabetes
developed urinary retention following treatment with BOTOX® 100 Units vs 0% of patients
(0/69) treated with placebo. In patients without diabetes, 6.3% of patients (33/526)
developed urinary retention following treatment with BOTOX® 100 Units vs 0.6% of
patients (3/516) treated with placebo.
Detrusor Overactivity Associated With a Neurologic Condition
In clinical trials, 30.6% of patients (33/108) who were not using clean intermittent
catheterization (CIC) prior to injection, required catheterization for urinary retention
following treatment with BOTOX® 200 Units as compared to 6.7% of patients (7/104)
treated with placebo. The median duration of postinjection catheterization for these
patients treated with BOTOX® 200 Units (n = 33) was 289 days (minimum 1 day to
maximum 530 days) as compared to a median duration of 358 days (minimum 2 days to
maximum 379 days) for patients receiving placebo (n = 7).
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).
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.
ADVERSE REACTIONS
Adverse reactions to BOTOX® for injection are discussed in greater detail in the following sections:
Boxed Warning, Contraindications, and Warnings and Precautions.
Overactive Bladder
The most frequently reported adverse reactions for overactive bladder occurring within
12 weeks of injection include urinary tract infection (BOTOX® 18%, placebo 6%),
dysuria (BOTOX® 9%, placebo 7%), urinary retention (BOTOX® 6%, placebo 0%),
bacteriuria (BOTOX® 4%, placebo 2%), and residual urine volume (BOTOX® 3%,
placebo 0%).
A higher incidence of urinary tract infection was observed in patients with diabetes
mellitus treated with BOTOX® 100 Units and placebo than nondiabetics.
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% vs 23%,
respectively.
Detrusor Overactivity Associated With a Neurologic Condition
The most frequently reported adverse reactions within 12 weeks of BOTOX® injection
for detrusor overactivity associated with a neurologic condition include urinary tract
infection (BOTOX® 24%, placebo 17%), urinary retention (BOTOX® 17%, placebo 3%), and hematuria (BOTOX® 4%, placebo 3%).
The following adverse event rates were reported at any time following initial injection
and prior to reinjection or study exit (median duration of 44 weeks of exposure): urinary
tract infections (49%), urinary retention (17%), constipation (4%), muscular weakness
(4%), dysuria (4%), fall (3%), gait disturbance (3%), and muscle spasm (2%).
Chronic Migraine
The most frequently reported adverse reactions following injection of BOTOX® for Chronic Migraine vs placebo include, respectively:
neck pain (9% vs 3%), headache (5% vs 3%), eyelid ptosis (4% vs < 1%), migraine (4% vs 3%), muscular weakness (4% vs < 1%), musculoskeletal
stiffness (4% vs 1%), bronchitis (3% vs 2%), injection-site pain (3% vs 2%), musculoskeletal pain (3% vs 1%), myalgia (3% vs 1%), facial
paresis (2% vs 0%), hypertension (2% vs 1%), and muscle spasms (2% vs 1%).
Severe worsening of migraine requiring hospitalization occurred in approximately 1% of BOTOX® treated patients in study 1 and study 2,
usually within the first week after treatment, compared with 0.3% of placebo-treated patients.
Upper Limb Spasticity
The most frequently reported adverse reactions following injection of BOTOX® for upper
limb spasticity include pain in extremity, muscle weakness, fatigue, nausea, and
bronchitis.
Lower Limb Spasticity
The most frequently reported adverse reactions following injection of BOTOX® for lower limb spasticity include arthralgia,
back pain, myalgia, upper respiratory tract infection, and injection site pain.
Cervical Dystonia
The most frequently reported adverse reactions following injection of BOTOX® for
Cervical Dystonia include dysphagia (19%), upper respiratory infection (12%), neck pain
(11%), and headache (11%).
Blepharospasm
The most frequently reported adverse reactions following injection of BOTOX® for
blepharospasm include ptosis (21%), superficial punctate keratitis (6%), and eye dryness (6%).
Strabismus
The most frequently reported adverse events following injection of BOTOX® for
strabismus include ptosis (15.7%) and vertical deviation (16.9%).
Primary Axillary Hyperhidrosis
The most frequently reported adverse events (3%-10% of adult patients) following
injection of BOTOX® for severe primary axillary hyperhidrosis include injection-site
pain and hemorrhage, nonaxillary sweating, infection, pharyngitis, flu syndrome,
headache, fever, neck or back pain, pruritus, and anxiety.
Postmarketing Experience
Adverse reactions that have been identified during postapproval use of BOTOX® are discussed in
greater detail in Postmarketing Experience (Section 6.3 of the Prescribing Information).
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.
DRUG INTERACTIONS
Co-administration of BOTOX® or other agents interfering with neuromuscular transmission
(eg, aminoglycosides, curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated.
Use of anticholinergic drugs after administration of BOTOX® may potentiate systemic anticholinergic effects. 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. Excessive weakness may also be
exaggerated by administration of a muscle relaxant before or after administration of BOTOX®.
Please see BOTOX® full Prescribing Information including Boxed Warning and Medication Guide.
