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be associated with the injection and occurred within the first week. The events were generally transient but may last several months or longer. (* incidence not different from Placebo) The data described in Table 2 reflect exposure to BOTOX® Cosmetic in 405 subjects aged 18 to 75 who were evaluated in the randomized, placebo-controlled clinical studies to assess the use of BOTOX® Cosmetic in the improvement of the appearance of glabellar lines [see Clinical Studies (14)]. Adverse events of any cause were reported for 44% of the BOTOX® Cosmetic treated subjects and 42% of the placebo treated subjects. The incidence of blepharoptosis was higher in the BOTOX® Cosmetic treated arm than in placebo (3% vs. 0). In the open-label, repeat injection study, blepharoptosis was reported for 2% (8/373) of subjects in the first treatment cycle and 1% (4/343) of subjects in the second treatment cycle. Adverse events of any type were reported for 49% (183/373) of subjects overall. The most frequently reported of these adverse events in the open-label study included respiratory infection, headache, flu syndrome, blepharoptosis, pain and nausea. Table 2: Adverse Events Reported at Higher Frequency (>1%) in the BOTOX® Cosmetic Group Compared to the Placebo Group Percent of Patients Reporting Adverse Events Adverse Events by Body System BOTOX® Cosmetic (N=405) % Placebo (N=130) % Overall 44 42 Body as a Whole Pain in Face 2 1 Skin and Appendages Skin Tightness 1 0 Digestive System Nausea Dyspepsia Tooth Disorder 3 1 1 2 0 0 Special Senses Blepharoptosis 3 0 Musculoskeletal System Muscle Weakness 2 0 Cardiovascular Hypertension 1 0 Immunogenicity 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. The rate of formation of neutralizing antibodies in patients receiving BOTOX® Cosmetic has not been well studied. 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. The critical factors for neutralizing antibody formation have not been well characterized. 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 with the incidence of antibodies to other products may be misleading. Post-marketing Experience 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 [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. 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; 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 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) DRUG INTERACTIONS No formal drug interaction studies have been conducted with BOTOX® Cosmetic (onabotulinumtoxinA) for injection. Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission 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. Anticholinergic Drugs Use of anticholinergic drugs after administration of BOTOX® Cosmetic may potentiate systemic anticholinergic effects. Other Botulinum Neurotoxin Products 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. Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of BOTOX® Cosmetic. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. BOTOX® Cosmetic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether BOTOX® Cosmetic is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BOTOX® Cosmetic is administered to a nursing woman. Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use The two clinical studies of BOTOX® Cosmetic did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, the responder rates appeared to be higher for patients younger than age 65 than for patients 65 years or older. OVERDOSAGE Excessive doses of BOTOX® Cosmetic (onabotulinumtoxinA) for injection may be expected to produce neuromuscular weakness with a variety of symptoms. Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection or oral ingestion occur or overdose be suspected, these patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization. The person should be medically supervised for several weeks for signs and symptoms of systemic muscular weakness which could be local, or distant from the site of injection [see Boxed Warning and Warnings and Precautions]. If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care. In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 1-770-488-7100. More information can be obtained at http://www.cdc.gov/mmwr/preview /mmwrhtml/mm5232a8.htm. Manufactured by: Allergan Pharmaceuticals Ireland a subsidiary of: Allergan, Inc. 2525 Dupont Dr. Irvine, CA 92612 © 2012 Allergan, Inc. ® marks owned by Allergan, Inc. 71823US16 APC06IG13