Included as part of the PRECAUTIONS section.
Lack Of Interchangeability Between Botulinum Toxin
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 [see DESCRIPTION].
Spread Of Toxin Effect
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.
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.
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.
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 preexisting cardiovascular
disease. Use caution when administering to patients with pre-existing
Increased Risk Of Clinically Significant Effects With
Pre-Existing Neuromuscular Disorders
Individuals with peripheral motor neuropathic diseases,
amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g.,
myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given
botulinum toxin. Patients with 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 [see Spread of Toxin Effect and Dysphagia and Breathing Difficulties].
Dysphagia And Breathing Difficulties
Treatment with BOTOX and other botulinum toxin products
can result in swallowing or breathing difficulties. Patients with preexisting
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 Spread of Toxin Effect].
Deaths as a complication of severe dysphagia have been
reported after treatment with botulinum toxin. Dysphagia may persist for
several months, and require use of a feeding tube to maintain adequate
nutrition and hydration. Aspiration may result from severe dysphagia and is a
particular risk when treating patients in whom swallowing or respiratory
function is already compromised.
Treatment with botulinum toxins may weaken neck muscles
that serve as accessory muscles of ventilation. This may result in a critical
loss of breathing capacity in patients with respiratory disorders who may have
become dependent upon these accessory muscles. There have been postmarketing
reports of serious breathing difficulties, including respiratory failure.
Patients with smaller neck muscle mass and patients who
require bilateral injections into the sternocleidomastoid muscle for the
treatment of cervical dystonia have been reported to be at greater risk for
dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce
the occurrence of dysphagia. Injections into the levator scapulae may be
associated with an increased risk of upper respiratory infection and dysphagia.
Patients treated with botulinum toxin may require
immediate medical attention should they develop problems with swallowing,
speech or respiratory disorders. These reactions can occur within hours to
weeks after injection with botulinum toxin [see Spread of Toxin Effect].
Pre-existing Conditions At The Injection Site
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).
Corneal Exposure And Ulceration In Patients Treated With
BOTOX For Blepharospasm
Reduced blinking from injection of BOTOX/BOTOX Cosmetic
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.
Ophthalmic Adverse Reactions In Patients Treated With BOTOX
There have been reports of dry eye, eye irritation,
photophobia, or visual changes associated with BOTOX Cosmetic injection in or
near the orbicularis oculi muscle. If these ocular signs and symptoms persist,
consider referring patients to an ophthalmologist [see Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm].
Spatial Disorientation, Double Vision Or Past-pointing In
Patients Treated For Strabismus
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.
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.
Patient Counseling Information
See FDA-approved patient
Provide a copy of the
Medication Guide and review the contents with the patient.
Swallowing, Speaking Or Breathing Difficulties, Or Other
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 [see BOXED
WARNING and WARNINGS AND PRECAUTIONS].
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
ocular symptoms including eye dryness, eye pain, eye irritation, or
photosensitivity, or changes in vision. Advise patients to report these
symptoms to the prescribers.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long term studies in animals have not been performed to
evaluate carcinogenic potential of BOTOX Cosmetic.
BOTOX Cosmetic was negative in a battery of in vitro (microbial
reverse mutation assay, mammalian cell mutation assay, and chromosomal
aberration assay) and in vivo (micronucleus assay) genetic toxicologic assays.
In fertility studies of BOTOX Cosmetic (4, 8, or 16
Units/kg) in which either male or female rats were injected intramuscularly
prior to mating and on the day of mating (3 doses, 2 weeks apart for males, 2
doses, 2 weeks apart for females) to untreated animals, reduced fertility was
observed in males at the intermediate and high doses and in females at the high
dose. The no-effect doses for reproductive toxicity (4 Units/kg in males, 8
Units/kg in females) are approximately 4-8 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).
Use In Specific Populations
There are no studies or adequate data from postmarketing
surveillance on the developmental risk associated with use of BOTOX Cosmetic in
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 [see Data].
In the U.S. general population, the estimated background
risk of major birth defects and miscarriages in clinically recognized
pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth
defects and miscarriage for the indicated populations is unknown.
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
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.
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.
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
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.
Safety and effectiveness in patients below the age of 18
years have not been established.
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 [see Clinical Studies].
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.
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.