Botox Adverse Reactions

Adverse Drug Reaction Overview: In general, adverse reactions occur within the first few days following injection and while generally transient may have duration of several months or, in rare cases, longer.
Local muscle weakness represents the expected pharmacological action of botulinum toxin in muscle tissue. However, weakness of adjacent muscles associated with local diffusion and/or injection technique has been reported. Muscle weakness remote to the site of injection and other serious adverse effects (e.g. dysphagia, aspiration pneumonia) have been rarely reported in both pediatric and adult patients, some associated with a fatal outcome.
As is expected for any injection procedure, localized pain, inflammation, paresthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localized infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
For each indication the frequency of adverse reactions documented during clinical trials is given. The frequency is defined as follows: Very Common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000; <1/100); Rare (≥1/10,000; <1/1,000); Very Rare (<1/10,000).
Blepharospasm/Hemifacial Spasm: Safety data compiled from controlled clinical trials and open label studies involving 1732 patients treated with BOTOX, the following adverse reactions were reported. (See Table 22.)

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Strabismus: Safety data compiled from clinical trials involving approximately 2058 patients treated with BOTOX. The following adverse reactions were reported. (See Table 23.)

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Cervical Dystonia: Safety data compiled from placebo controlled, double-blind trial involving 231 patients treated with BOTOX. The following adverse reactions were reported. (See Table 24.)

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Pediatric Cerebral Palsy: Safety data were compiled from two double-blind, randomized, placebo controlled and an open-label extension studies involving approximately 304 patients treated with BOTOX. The following adverse reactions were reported. (See Table 25.)

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Upper Limb Spasticity in Adults: Safety data compiled from double-blind and open label studies involving 339 patients treated with BOTOX. The following adverse reactions were reported. (See Table 26.)

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Lower limb spasticity in Adults: Safety data were compiled from double-blind, placebo-controlled, clinical studies involving 538 adult lower limb spasticity patients treated with BOTOX. The most frequently reported adverse reactions reported by ≥1% of BOTOX treated patients and more frequent than in placebo-treated are listed as follows. No change was observed in the overall safety profile with repeat dosing. (See Table 27.)

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Primary Hyperhidrosis of the Axillae: Safety data compiled from double-blind and open-label studies involving 397 patients treated with BOTOX. The following adverse reactions were reported. (See Table 28.)

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Note: increase in non-axillary sweating was reported in 4.5% of patients within one month after injection and showed no pattern with respect to anatomical sites affected. Resolution was seen in approximately 30% of the patients within four months.
Upper Facial Lines (Glabellar Lines, Crow's Feet, Forehead Lines): Glabellar Lines: Safety data were compiled from two double-blind, placebo-controlled, multicenter studies involving 405 patients treated with BOTOX. The following adverse events were reported. (See Table 29.)

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Crows' Feet Lines: Safety data compiled from clinical studies treated with BOTOX. The following adverse reactions were reported. (See Table 30.)

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Forehead Lines: The table as follows presents the most frequently reported adverse reactions in double-blind, placebo-controlled clinical studies following injection of BOTOX for forehead lines with glabellar lines. (See Table 31.)

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There were no additional adverse drug reactions reported with the simultaneous treatment of Facial Lines (inclusive of forehead lines, glabellar lines, and crow's feet lines).
Chronic Migraine: Safety data compiled from two double-blind, placebo controlled studies involving 687 patients treated with 155 U - 195 U of BOTOX. The following adverse reactions were reported. (See Table 32.)

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Migraine, including worsening migraine, was reported in 3.8% of BOTOX and 2.6% of placebo patients, typically occurring within the first month after treatment. These reactions did not consistently reoccur with subsequent treatment cycles, and the overall incidence decreased with repeated treatments.
The discontinuation rate due to adverse events in these phase 3 trials was 3.8% for BOTOX vs. 1.2% for placebo. The most frequently reported adverse events leading to discontinuation in the BOTOX group were neck pain (0.6%), muscular weakness (0.4%), headache (0.4%), and migraine (0.4%).
Overactive Bladder: The table as follows presents the most frequently reported adverse reactions in double-blind, placebo-controlled, pivotal Phase 3 studies within 12 weeks of injection for overactive bladder. (See Table 33.)

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During the complete treatment cycle, the following adverse reactions with BOTOX 100 Units were reported: urinary tract infections (26%), dysuria (11%), bacteriuria (8%), urinary retention (6%), residual urine volume (3%), and pollakiuria (2%).
Events considered to be procedure-related by the investigator reported at any time following initial injection were dysuria (6%) and hematuria (2%).
Catheterization was initiated in 6.5% following treatment with BOTOX 100 Units versus 0.4% in the placebo group.
No change was observed in the overall safety profile with repeat dosing.
Neurogenic Detrusor Overactivity: The table as follows 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. (See Table 34.)

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The following adverse event rates with BOTOX 200 U 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%), fatigue (6%), haematuria* (5%), constipation (4%), muscular weakness (4%), dysuria* (4%), fall (3%), gait disturbance (3%), insomnia (3%), muscle spasm (2%), autonomic dysreflexia* (2%), and bladder diverticulum (1%). No change was observed in the overall safety profile with repeat dosing.
*procedure-related events.
In the multiple sclerosis (MS) patients enrolled in the pivotal studies, 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.
Among patients who were not catheterizing at baseline prior to treatment, catheterization was initiated in 38.9% following treatment with BOTOX 200 U versus 17.3% on placebo. Catheterization rates by etiology (multiple sclerosis [MS] and spinal cord injury [SCI]) are further presented in the table as follows. (See Table 35.)

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In the clinical trials, no change in the type of adverse reactions was observed following two treatments.
Abnormal Hematologic and Clinical Chemistry Findings: No specific trends in abnormal hematologic or clinical chemistry findings have been reported.
Post-Market Adverse Drug Reactions: There have been rare spontaneous reports of death, sometimes associated with anaphylaxis, dysphagia, respiratory compromise, pneumonia, and/or other significant debility, after treatment with BOTOX.
Serious and/or immediate hypersensitivity reactions such as anaphylaxis and serum sickness have been rarely reported, as well as other manifestations of hypersensitivity including urticaria, soft tissue edema, and dyspnea. Some of these reactions have been reported following the use of BOTOX either alone or in conjunction with other products associated with similar reactions. One fatal case of anaphylaxis has been reported in which the patient died after being injected with BOTOX inappropriately diluted with 5 ml of 1% lidocaine. The causal role of BOTOX, lidocaine, or both cannot be reliably determined.
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. New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events.
Angle closure glaucoma has been reported very rarely following BOTOX treatment for blepharospasm.
Lagophthalmos has been reported following BOTOX injection into the glabellar lines or crow's feet lines.
Eyelid edema has been reported following periocular BOTOX injection.
These reactions are reported voluntarily from a population of uncertain size. The exact relationship of these events to the botulinum toxin injection has not been established.
The following list includes adverse drug reactions or other medically relevant adverse events that have been reported since the drug has been marketed, regardless of indication, and may be in addition to those cited in PRECAUTIONS, and previously mentioned texts: denervation/muscle atrophy; respiratory depression and/or respiratory failure; dyspnea; aspiration pneumonia; dysarthria; dysphonia; dry mouth; strabismus; peripheral neuropathy; abdominal pain; diarrhea; nausea; vomiting; pyrexia; anorexia; vision blurred; visual disturbance, hypoacusis; tinnitus; vertigo; facial palsy, facial paresis; brachial plexopathy; radiculopathy; syncope; hypoesthesia; malaise; myalgia; myasthenia gravis; paresthesia; rash, erythema multiforme; pruritus; dermatitis psoriasiform; hyperhidrosis; alopecia, including madarosis, dry eye, and localized muscle twitching/involuntary muscle contractions.