The following adverse reactions to BOTOX (onabotulinum toxin A) For Injection are discussed in greater detail in other sections of the labeling:
- Spread of Toxin Effects [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
- Dysphagia and Breathing Difficulties in Treatment of Cervical Dystonia [see WARNINGS AND PRECAUTIONS]
- Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity [see WARNINGS AND PRECAUTIONS]
- Urinary Retention in Patients Treated for Bladder Dysfunction [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, but with different labeled Indications and Usage. Therefore, adverse reactions observed with the use of BOTOX Cosmetic also have the potential to be observed with the use of BOTOX.
In general, adverse reactions occur within the first week following injection of BOTOX and while generally transient, may have a duration of several months or longer. Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising may be associated with the injection. Needle-related pain and/or anxiety may result in vasovagal responses (including e.g., syncope, hypotension), which may require appropriate medical therapy.
Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of nearby muscles may also occur due to spread of toxin [see WARNINGS AND PRECAUTIONS].
Table 10 presents the most frequently reported adverse reactions in double-blind, placebo-controlled clinical trials for overactive bladder occurring within 12 weeks of the first BOTOX treatment.
Table 10: Adverse Reactions Reported by ≥ 2% of BOTOX treated Patients and More Often than in Placebo-treated Patients Within the First 12 Weeks after Intradetrusor Injection, in Double-blind, Placebo-controlled Clinical Trials in Patients with OAB
|Adverse Reactions||BOTOX 100 Units
|Urinary tract infection||99 (18%)||30 (6%)|
|Dysuria||50 (9%)||36 (7%)|
|Urinary retention||31 (6%)||2 (0%)|
|Bacteriuria||24 (4%)||11 (2%)|
|Residual urine volume*||17 (3%)||1 (0%)|
|*Elevated PVR not requiring catheterization. Catheterization was required for PVR ≥ 350 mL regardless of symptoms, and for PVR ≥ 200 mL to < 350 mL with symptoms (e.g. voiding difficulty).|
A higher incidence of urinary tract infection was observed in patients with diabetes mellitus treated with BOTOX 100 Units and placebo than in patients without diabetes, as shown in Table 11.
Table 11: Proportion of Patients Experiencing Urinary Tract Infection following an Injection in Double-blind, Placebo-controlled Clinical Trials in OAB according to history of Diabetes Mellitus
|Patients with Diabetes||Patients without Diabetes|
|Botox 100 Units
|Botox 100 Units
|Urinary tract infection (UTI)||25 (31%)||8 (12%)||135 (26%)||51 (10%)|
The incidence of UTI increased in patients who experienced a maximum post-void residual (PVR) urine volume > 200 mL following BOTOX injection compared to those with a maximum PVR < 200 mL following BOTOX injection, 44% versus 23%, respectively. No change was observed in the overall safety profile with repeat dosing during an open-label, uncontrolled extension trial.
Detrusor Overactivity associated with a Neurologic Condition
Table 12 presents the most frequently reported adverse reactions in double-blind, placebo-controlled studies within 12 weeks of injection for detrusor overactivity associated with a neurologic condition.
Table 12: Adverse Reactions Reported by ≥ 2% of BOTOX treated Patients and More Frequent than in Placebo-treated Patients Within the First 12 Weeks after Intradetrusor Injection in Double-blind, Placebo-controlled Clinical Trials
|Adverse Reactions||BOTOX 200 Units
|Urinary tract infection||64 (24%)||47 (17%)|
|Urinary retention||45 (17%)||8 (3%)|
|Hematuria||10 (4%)||8 (3%)|
The following adverse reactions with BOTOX 200 Units were reported at any time following initial injection and prior to re-injection 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%).
In the MS patients enrolled in the double-blind, placebo-controlled trials, the MS exacerbation annualized rate (i.e., number of MS exacerbation events per patient-year) was 0.23 for BOTOX and 0.20 for placebo.
No change was observed in the overall safety profile with repeat dosing.
In double-blind, placebo-controlled chronic migraine efficacy trials (Study 1 and Study 2), the discontinuation rate was 12% in the BOTOX treated group and 10% in the placebo-treated group. Discontinuations due to an adverse event were 4% in the BOTOX group and 1% in the placebo group. The most frequent adverse events leading to discontinuation in the BOTOX group were neck pain, headache, worsening migraine, muscular weakness and eyelid ptosis.
The most frequently reported adverse reactions following injection of BOTOX for chronic migraine appear in Table 13.
Table 13: Adverse Reactions Reported by ≥ 2% of BOTOX treated Patients and More Frequent than in Placebo-treated Patients in Two Chronic Migraine Double-blind, Placebo-controlled Clinical Trials
|BOTOX 155 Units-195 Units
|Nervous system disorders|
|Headache||32 (5%)||22 (3%)|
|Migraine||26 (4%)||18 (3%)|
|Facial paresis||15 (2%)||0 (0%)|
|Eyelid ptosis||25 (4%)||2 ( < 1%)|
|Infections and Infestations|
|Bronchitis||17 (3%)||11 (2%)|
|Musculoskeletal and connective tissue disorders|
|Neck pain||60 (9%)||19 (3%)|
|Musculoskeletal stiffness||25 (4%)||6 (1%)|
|Muscular weakness||24 (4%)||2 ( < 1%)|
|Myalgia||21 (3%)||6 (1%)|
|Musculoskeletal pain||18 (3%)||10 (1%)|
|Muscle spasms||13 (2%)||6 (1%)|
|General disorders and administration site conditions|
|Injection site pain||23 (3%)||14 (2%)|
|Hypertension||11 (2%)||7 (1%)|
Other adverse reactions that occurred more frequently in the BOTOX group compared to the placebo group at a frequency less than 1% and potentially BOTOX related include: vertigo, dry eye, eyelid edema, dysphagia, eye infection, and jaw pain. 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 to 0.3% of placebo-treated patients.
Upper Limb Spasticity
The most frequently reported adverse reactions following injection of BOTOX for adult spasticity appear in Table 14.
Table 14: Adverse Reactions Reported by ≥ 2% of BOTOX treated Patients and More Frequent than in Placebo-treated Patients in Adult Spasticity Double-blind, Placebo-controlled Clinical Trials
|Adverse Reactions by System Organ Class||BOTOX 251 Units- 360 Units
|BOTOX 150 Units- 250 Units
|BOTOX < 150 Units
|Nausea||3 (3%)||3 (2%)||1 (2%)||1 (1%)|
|General disorders and administration site conditions|
|Fatigue||4 (3%)||4 (2%)||1 (2%)||0|
|Infections and infestations|
|Bronchitis||4 (3%)||4 (2%)||0||2 (1%)|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||7 (6%)||10 (5%)||5 (9%)||8 (4%)|
|Muscular weakness||0||7 (4%)||1 (2%)||2 (1%)|
In cervical dystonia patients evaluated for safety in double-blind and open-label studies following injection of BOTOX, the most frequently reported adverse reactions were dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%).
Other events reported in 2-10% of patients in any one study in decreasing order of incidence include: increased cough, flu syndrome, back pain, rhinitis, dizziness, hypertonia, soreness at injection site, asthenia, oral dryness, speech disorder, fever, nausea, and drowsiness. Stiffness, numbness, diplopia, ptosis, and dyspnea have been reported.
Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of BOTOX resulting from the spread of the toxin outside the injected muscles [see WARNINGS AND PRECAUTIONS].
The most common severe adverse reaction associated with the use of BOTOX injection in patients with cervical dystonia is dysphagia with about 20% of these cases also reporting dyspnea [see WARNINGS AND PRECAUTIONS]. Most dysphagia is reported as mild or moderate in severity. However, it may be associated with more severe signs and symptoms [see WARNINGS AND PRECAUTIONS].
Additionally, reports in the literature include a case of a female patient who developed brachial plexopathy two days after injection of 120 Units of BOTOX for the treatment of cervical dystonia, and reports of dysphonia in patients who have been treated for cervical dystonia.
Primary Axillary Hyperhidrosis
The most frequently reported adverse reactions (3-10% of adult patients) following injection of BOTOX in double-blind studies included injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety.
The data reflect 346 patients exposed to BOTOX 50 Units and 110 patients exposed to BOTOX 75 Units in each axilla.
In a study of blepharospasm patients who received an average dose per eye of 33 Units (injected at 3 to 5 sites) of the currently manufactured BOTOX, the most frequently reported adverse reactions were ptosis (21%), superficial punctate keratitis (6%), and eye dryness (6%).
Other events reported in prior clinical studies in decreasing order of incidence include: irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia, entropion, diffuse skin rash, and local swelling of the eyelid skin lasting for several days following eyelid injection.
In two cases of VII nerve disorder, reduced blinking from BOTOX injection of the orbicularis muscle led to serious corneal exposure, persistent epithelial defect, corneal ulceration and a case of corneal perforation. Focal facial paralysis, syncope, and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm.
Extraocular muscles adjacent to the injection site can be affected, causing vertical deviation, especially with higher doses of BOTOX. The incidence rates of these adverse effects in 2058 adults who received a total of 3650 injections for horizontal strabismus was 17%.
The incidence of ptosis has been reported to be dependent on the location of the injected muscles, 1% after inferior rectus injections, 16% after horizontal rectus injections and 38% after superior rectus injections.
In a series of 5587 injections, retrobulbar hemorrhage occurred in 0.3% of cases.
As with all therapeutic proteins, there is a potential for immunogenicity. Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin.
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%), no patients among 406 migraine patients, no patients among 615 overactive bladder patients, and no patients among 475 detrusor overactivity associated with a neurologic condition patients with analyzed specimens developed the presence of neutralizing antibodies.
The data reflect the patients whose test results were considered positive or negative for neutralizing activity to BOTOX in a mouse protection assay. The results of these tests are 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 neutralizing activity to BOTOX with the incidence of antibodies to other products may be misleading.
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.
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; aspiration pneumonia; brachial plexopathy; denervation/muscle atrophy; diarrhea; dry mouth; dysarthria; dyspnea; facial palsy; facial paresis; hyperhidrosis; hypoacusis; hypoaesthesia; localized numbness; malaise; muscle weakness; myalgia; myasthenia gravis; nausea; paresthesia; peripheral neuropathy; pruritis; pyrexia; radiculopathy; respiratory depression and/or respiratory failure; skin rash (including erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption); strabismus; syncope; tinnitus; vertigo; vision blurred; visual disturbances; and vomiting.
There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin [see WARNINGS AND PRECAUTIONS].
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.