appendix 5 Side-effects and contraindications to BoNTA injections

Physicians are instructed to have their patients read the Medication Guide that is packaged with onabotulinumtoxinA before treatment and before each subsequent treatment. This information does not take the place of the patient talking with their physician about their medical condition or their treatment. Patients are encouraged to share this information with their family members and caregivers.

OnabotulinumtoxinA (BOTOX® Cosmetic) is approved by the Food and Drug Administration (FDA) only to treat and temporarily improve moderate to severe glabellar frown lines in adults younger than 65 years of age. It is not known whether onabotulinumtoxinA is safe or effective in children younger than 18 years of age for the treatment of axillary hyperhidrosis, the only area on the body FDA approved for the treatment of hyperhidrosis. OnabotulinumtoxinA or abobotulinumtoxinA is not recommended for use in children younger than 18 years of age.

POTENTIAL SIDE-EFFECTS OF ONABOTULINUMTOXINA

INJECTIONS (1,2)

I.Adverse effects of limited duration that are common, localized, and not of a serious nature:

Common with any percutaneous injection

•Mild stinging, burning or pain with injection

•Edema around injection site

•Erythema around injection site

•Mild headache, localized and transient

Technique-dependent

•Ecchymosis lasting 3 to 10 days

•Asymmetry

•Oral incompetence and asymmetric smile

•Lack of neck strength

•Lack of intended cosmetic effect

Rare and idiosyncratic

•Numbness and paresthesias, localized and transient

•Focal tonic movements (twitching)

•Mild nausea and occasional vomiting

•Dizziness or syncope

•Mild malaise and myalgias (localized and generalized)

•Dry mouth

•Periorbital edema

II. Adverse effects of longer duration that can be serious and are technique-dependent

•Blepharoptosis

•Brow ptosis

•Diplopia

•Blurred vision or diminished visual acuity

•Diminished tearing and xeropthalmia with or without keratitis

•Ectropion (can lead to xeropthalmia)

•Lagopthalmus (can lead to exposure keratitis)

•Dysphagia

•Dysarthria

•Dysphonia

III. Adverse effects of longer duration that can be serious and are not technique-dependent

Immediate hypersensitivity reactions

•Urticaria, pruritus, rash, or generalized erythema

•Dyspnea, wheezing, or exacerbation of asthma

•Soft tissue edema

•Anaphylaxis

Contraindications to OnabotulinumtoxinA Injections

Patients should not be treated or otherwise treated with extreme caution who are

•Psychologically unstable or who have questionable motives and unrealistic expectations

•Dependent on intact facial movements and expressions for their livelihood (e.g., actors, singers, musicians and other media personalities)

•Afflicted with peripheral motor neuropathic disease, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g. myasthenia gravis, or Lambert-Eaton syndrome)

•Allergic to any of the component ingredients of BoNTA or BoNTB (i.e., BoNT, human albumin, saline, lactose and sodium succinate)

•Taking certain medications that can interfere with neuromuscular impulse transmission and potentiate the effects of BoNT (e.g. aminoglycosides, penicillamine, quinine, and calcium channel blockers)

•Pregnant or lactating (BoNTs are classified as pregnancy category C drugs)

•Experiencing an active skin infection at the planned injection site

POTENTIAL BENEFICIAL EFFECTS OF ONABOTULINUMTOXINA OR

ABOBOTULINUMTOXINA INJECTIONS

•Relief of frontal or occipital “tension headaches”

•Relief of migraine headaches

•Compensatory muscle strengthening of the same muscles when segmentally treated (e.g., strengthening of the lower frontalis and elevation of the eyebrows when the upper frontalis is treated or improvement of posture and projection of breasts when the lower pectoralis major or minor are treated)

•Compensatory muscle strengthening of synergistic muscles (e.g., strengthening of the lip levators and depressors when the orbicularis oris is treated)

•Compensatory muscle strengthening of antagonistic muscles (e.g., strengthening of the lower frontalis and medial brow lift when the medial brow depressors are treated or lateral brow lift when lateral brow depressors are treated

RISK EVALUATION AND MITIGATION STRATEGY

In 2009, when another BoNTA (DysportTM; abobotulinumtoxinA) was approved by the FDA for use in the United States, Allergan, Inc. instituted a surveillance program called Risk Evaluation and Mitigation Strategy (REMS) to update its physician injectors on safety issues regarding the use of BOTOX®/BOTOX® Cosmetic

(onabotulinumtoxinA). The goals of the REMS program are to minimize the risks of medication errors related to the lack of interchangeability of onabotulinumtoxinA units with those of licensed botulinum toxins of other manufacturers and to inform prescribers and patients about the potential occurrence of spread of toxin effect beyond the injection site.

Physician injectors are advised to discuss the risks associated with onabotulinumtoxinA therapy outlined above and in the Medication Guide for onabotulinumtoxinA with patients and all the health care personnel who are involved in the preparation, prescribing, and/ or injection of onabotulinumtoxinA. According to FDA regulations, a copy of the Medication Guide must be distributed directly to each patient every time he or she receives an onabotulinumtoxinA injection. Copies of the onabotulinumtoxinA Medical Guide can be obtained by calling 1-800-433-8871 or printing copies directly from the websites www.botoxmedical.com or www.botoxcosmetic. com. A copy of the Medication Guide also is included in every carton of onabotulinumtoxinA.

Because there are currently multiple marketed botulinum toxin products with different dose to potency ratios, there is a concern about medication errors such as overdosing based on incorrect unit administration from interchanging different BoNTA products (3). It is important to understand that BOTOX®/BOTOX® Cosmetic (onabotulinumtoxinA; Allergan, Inc.), MYOBLOCTM (rimabotulinumtoxinB, Solstice), and DysportTM (abobotulinumtoxinA; Ipsen Biopharm Limited/Medicis Corporation) are unique biologic products that are not interchangeable with each other. The potency units of onabotulinumtoxinA are specific to the preparation and assay method utilized. Therefore, units of biological activity of onabotulinumtoxinA cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method. Additionally, onabotulinumtoxinA has multiple indications which all require specific dosing. Caution should be taken to ensure that the dosing, dilution, injection volume, and injection patterns are appropriate for the product and the patient.

No definitive reports of serious adverse events of distant spread of toxin effect associated with the cosmetic and dermatologic use of onabotulinumtoxinA have been reported when the recommended labelled dose of 20 units for glabellar lines or 100 units for severe primary axillary hyperhidrosis have been used.

Distant Spread of Toxin Effect (3)

Postmarketing reports indicate that the effect of onabotulinumtoxinA and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, 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. This risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses. However, at the lower doses generally used for cosmetic purposes, there have been no substantiated reports of life-threatening adverse results. Furthermore, using currently available analytical technology, it is not possible to detect onabotulinumtoxinA in the peripheral blood following intramuscular injections at the currently recommended doses found in this compendium on the BoNTs. A thorough review and understanding of the current package insert for the brand of BoNT to be used is highly recommended before treating patients.

REFERENCES

1. Coté TR, Mohan AK, Polder JA, Walton MK, Bruan MM. Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. JAAD 2005; 53: 407–15.

2. Gershon SK, Wise RP, Braun MM. Adverse events reported with cosmetic use of Botulinum toxin A. Pharmacoepidemiol Drug Safety 2001; 10(Suppl): S135–6.

3. Allergan, Inc. Botox Cosmetic (botulinum toxin type A) purified neurotoxin complex (Package Insert). Irvin, California: Allergan, Inc., revised August 2009.

282

perioral rhytides complications, 150–4 dilution, 146 dosing, 146–8

functional anatomy, 141–6 outcomes, 148–50

problem assessment and patient selection, 140–1

pharmocology

mechanism of action, 2–5 nonmotor anticholinergic effects, 5 retrograde transport, 5

physician’s negligence, 265 plantar hyperhidrosis, 254 platysma, 19, 140, 144

complications, 176–9 decussating, 181 dilution, 174 dosing, 176

functional anatomy, 173–4 injection sites, 238 outcomes, 176

problem assessment and patient selection, 173

postherpetic neuralgia (PHN), 225–28

postinjection ecchymoses, 97 preparation: BOTOX→, 272 primary focal hyperhidrosis, 248 procerus, 31

prolonged massage, 58 pseudoaugmentation, 148–9 pseudoblepharoptosis, 45 pseudoherniation, 98 Purtox, 238

quadratus labii superioris, 123, 126

Rated Numeric Kinetic Line Scale (RNKLS), 241–2

Raynaud’s phenomenon, 223–4

reflex sympathetic dystrophy syndrome (RSDS), 228–30

results

asymmetric smile, 156–7

INDEX

central brow frown lines, 41–2 chest wrinkling, 186–7

chin puckering, 169 cosmetic calf slimming, 218 deep mental crease, 169

exaggerated upper gummy smile, 136–8 forehead lines, 58–9

jawline blunting, 176 keloid formation, 199–202 lateral canthal lines, 72–3 lateral eyebrow lift, 82–3 lower eyelid lines, 91–2 melomental folds, 163 nasal flare, 111–12

nasal tip ptosis, 116 nasoglabellar lines, 106–7 nasolabial folds, 125–8 perioral rhytides, 148–50 platysma, 176

rimabotulinumtoxinB, 240–5

Risk Evaluation and Mitigation Strategy (REMS), 276–7

risorius (laughter muscle), 68, 69 Ross syndrome, 257–8

scar

hypertrophic, 229 keloid, 197–8, 228

Microbotox technique, 197 self-esteem, XII

serotypes, 1, 240, 241

Smith-Kettlewell Eye Research Institute, 1 soluble N-ethylmaleimide-sensitive factor

attachment protein receptor (SNARE), 15

sphincteric type muscle, 66 square jaws, 206 squinting, 66

standard of care, 264–5 static wrinkles, 140–1, 184 storage: BOTOX®, 272 submandibular gland, 209 substance P (SP), 224

superficial muscular aponeurotic system (SMAS), 15, 173

sweating, 190, 248 compensatory, 257 gustatory, 255–6

synaptobrevin, 240 systemic anticholinergic

drugs, 249

topical botulinum toxin, 238 transient receptor potential vanilloid

receptor-1 (TRPV1), 11 translocation, 3

transverse nasalis, 104, 105, 106 transverse rhytide, 133 triamcinolone, 198

turkey neck deformity, 180

upper face, 15–16, 18 upper gum mucosa, 132 upper lip levators, 138

vascular supply, 23 vasoconstrictor, 223 vasodilator, 223

vesicle associated membrane protein (VAMP), 240

vibratory anesthesia, 253 visual analog scale (VAS), 223,

226, 227

wicked witch’s chin, 166 wound healing, 198

Wrinkle Improvement Scale (WIS), 241 wrinkling

chest, 186–8

static and dynamic, 140

xerophthalmia (dry eye), 83

younger patients: forehead lines, 51 youthful face, 206

zygomatic arch, 73, 94, 130, 206, 207 zygomaticus muscles, 129