appendix 2 The preparation, handling, storage, and mode of injection of onabotulinumtoxinA

STORAGE OF ONABOTULINUMTOXINA

BOTOX®/BOTOX® Cosmetic (onabotulinumtoxinA) is a purified neurotoxin complex distributed in vials of 100 U or 50 U of sterile, vacuum-dried crystalline powder without preservative. The vials of onabotulinumtoxinA have a holographic film on the vial label with the name “Allergan” within the horizontal lines of rainbow color. They are shipped frozen in insulated, styrofoam containers containing dry ice. When they reach their destination, the vials of onabotulinumtoxinA can be stored in their dry, powdered form in the refrigerator at a constant temperature of 2°C to 8°C for up to 36 months for the 100 U vial and 24 months for the 50 U vial (1). Once reconstituted, the solution of onabotulinumtoxinA can be stored again in the refrigerator at a constant temperature of 2°C to 8°C. DO NOT REFREEZE RECONSTITUTED ONABOTULINUMTOXINA. Although the package insert for onabotulinumtoxinA recommends the reconstituted product be used within 4 hours, studies have shown that after reconstitution, the potency of onabotulinumtoxinA should remain consistent and unchanged for up to 6 weeks, and can be used without any noticeable change in clinical efficacy (2,3).

PREPARATION OF ONABOTULINUMTOXINA

The package insert for onabotulinumtoxinA suggests that the 100 U vial be reconstituted with 2.5 ml of 0.9% nonpreserved saline for a final concentration of 4 U/0.1 ml and the 50 U vial with 2.25 ml of the same (1). The report of a consensus conference of key physician injectors held in 2004 recommended that a 100 U vial of onabotulinumtoxinA be reconstituted at a “dilution that minimizes the likelihood of diffusion to neighboring muscle groups”, and can be anywhere from 1 to 10 ml of normal saline for each 100 U vial of product (4). Anecdotal and published reports suggest that volume may influence duration of effect, in that the greater the volume, the shorter the duration of effect (5). A recent study treating the glabella with onabotulinumtoxinA diluted with 1 ml/vial, 3 ml/vial, 5 ml/vial, and 10 ml/vial resulted in no significant differences on the Facial Wrinkle Scale as assessed by trained observers. However, subject assessment of the duration of effect was felt to be longer with the more concentrated onabotulinumtoxinA that was injected (6). The 2004 consensus conference report also attested to the fact that the majority of dermatologic and esthetic physician injectors reconstitute onabotulinumtoxinA with preserved normal saline instead of nonpreserved diluent. The result of a bilateral, comparative prospective study has shown that there is less pain with injection when preserved isotonic saline is used instead of nonpreserved isotonic saline (4,5,7). There was no loss of efficacy nor duration of potency whether onabotulinumtoxinA was reconstituted with preserved or unpreserved normal saline. Once reconstituted, the vial of onabotulinumtoxinA should be clear, colorless, and free of particulate matter, regardless of diluent and amount used (1).

HANDLING OF ONABOTULINUMTOXINA

Concerns over a potential loss of potency resulting from rough handling, agitation, and foaming during reconstitution were also addressed at the 2004 consensus conference (4). Trindade de Almeida et al. treated one side of six patients in the glabella and periocular area with onabotulinumtoxinA that was reconstituted by agitation to the point of bubbling and foaming, and the opposite side with onabotulinumtoxinA

that was not agitated (8). There was no difference in muscle relaxation between the two sides treated, and the duration of effect remained constant on both sides for approximately 16 weeks. Similar results were anecdotally confirmed by the majority of those present at the 2004 consensus conference (4).

INJECTION TECHNIQUE OF ONABOTULINUMTOXINA

OnabotulinumtoxinA should be injected with sterile, plastic, single-use syringes. In order to minimize the pain and bruising of injection, the use of tuberculin syringes with a 30 to 32G needle is recommended. For those injectors who want to reconstitute onabotulinumtoxinA with a minimum amount of diluent (1 ml or less) and be able to control the minutest amount of solution injected, an insulin syringe with an attached 29 or 31G needle can be used (9) (Becton-Dickinson, Franklin Lakes, New Jersey). Insulin syringes (0.5 or 0.3ml) have no potential space at the hub where the needle is preattached, thereby minimizing any wastage of solution (10). In addition, the barrel of the syringe is scored with markings representing 0.01ml that can be easily seen and which will correspond to 1 U of onabotulinumtoxinA when a 100 U vial is reconstituted with 1ml of diluent (9). To further reduce some of the discomfort associated with any type of intramuscular injection, the pretreatment application of either a topical anesthetic, ice, or both on the skin surface at the injection site can help provide a more comfortable, positive experience for some patients.

Although there are no controlled studies to support certain commonly prescribed posttreatment recommendations made to prevent local diffusion of the onabotulinumtoxinA beyond the injection site, many expert physician injectors still recommend the following for their patients:

1.DO NOT massage the onabotulinumtoxinA treated areas for 2 to 3 hours.

2.DO NOT bend over (e.g., to tie shoes or pick up something from the floor) for 2 to 3 hours after a onabotulinumtoxinA treatment of the upper face.

3.LIMIT heavy physical activity, and lying down or sleeping for 2 to 3 hours after a an onabotulinumtoxinA treatment of the upper face.

4.DO contract treated muscles for 2 to 3 hours immediately after an onabotulinumtoxinA treatment. This promotes the uptake of onabotulinumtoxinA by the receptor sites at the neuromuscular junctions.

Postmarketing reports indicate that the effects of onabotulinumtoxinA and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects (1). These symptoms have been reported hours to weeks after injection. The risk of symptoms is probably greatest in children treated for spasticity but symptoms also can 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 and approved indications, cases of the spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses but not at the lower doses generally used for

REFERENCES

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

2.Garcia A, Fulton JE Jr. Cosmetic denervation of the muscles of facial expression with botulinum toxin: a dose-response study. Dermatol Surg 1996; 22: 39.

3.Hexsel DM, de Almeida AT, Rutowitsch M et al. Multicenter, doubleblind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003; 29: 523.

4.Carruthers J, Fagien S, Matarasso SL. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics, Suppl Plast Reconstr Surg 2004; 114: 2S.

5.Klein AW. Complications and adverse reactions with the use of botulinum toxin. Dis Mon 2002; 48: 336.

6.Carruthers A, Carruthers J, Cohen J. Dilution volume of botulinum toxin type A for the treatment of glabellar rhytides: does it matter? Dermatol Surg 2007; 33: S97–S104.

7.Alam M, Dover JS, Arndt KA. Pain associated with injection of botulinum A exotoxin reconstituted using isotonic sodium chloride with and without preservative: a double-blind, randomized controlled trial. Arch Dermatol 2002; 138: 510.

8.Trindade de Almeida AR, Kadunc BV, Di Chiacchio N, Neto DR. Foam during reconstitution does not affect the potency of botulinum toxin type A. Dermatol Surg 2003; 29: 530.

9.Flynn TC, Carruthers A, Carruthers J. Surgical pearl: the use of the Ultra-Fine II short needle 0.3 cc insulin syringe for botulinum toxin injections. J Am Acad Dermatol 2002; 46: 931–3.

10.Hsu, JS, Dover, JS, and Arndt, KA. Effect of volume and concentration on the diffusion of botulinum exotoxin A. Arch Dermatol 2004; 140: 1351–4.

RATIONALE

I am aware that when a small amount of purified Botulinum neurotoxin A (BoNTA) is injected into a muscle, it causes weakness of that muscle. This occurs in 3 to 5 days or even later, and usually lasts 3 to 5 months but can last for shorter or longer amounts of time, depending on which BoNTA product is used and where it is injected.

Frown lines between the eyebrows are due to contraction of muscles around and between the eyebrows. Injecting BoNTA into this area will temporarily weaken these muscles causing a reduction or disappearance of the frown lines. Similarly, crow’s feet and horizontal forehead lines can be improved by injecting BoNTA into these areas, weakening the muscles that cause the wrinkles on the forehead and around the eyes. Many other areas of the central and lower face, neck, and chest also can be treated successfully with BoNTA, but treatment of any area other than between the eyebrows is currently not approved by the Food and Drug Administration (FDA) and is performed off-label.

RESULTS AND AFTER TREATMENT CARE

1.I understand that I will not be able to “frown” or see certain wrinkles while the injections of BoNTA into this area and other areas are effective. After a period of months wrinkles will return, at which time retreatment is appropriate and needed in order to maintain the previously treated area(s) without wrinkles.

2.I understand that I must remain upright and not bend or lower my head (i.e., to tie my shoes or pick up something), and I must not manipulate or rub the treated areas for 2 to 3 hours after my treatment session.

3.I understand I might experience quicker results if I repeatedly contract and use (e.g., frown) the injected muscles for the 2 to 3 hours after my treatment session.

RISKS AND COMPLICATIONS

The most common side effects associated with BoNTA injections for wrinkle correction are bruising and swelling. These local reactions are temporary. Less commonly, headache, numbness, temporary drooping of one or both eyebrows or eyelids, the enlargement of skin folds under the eyelids, or asymmetry can occur in 2% of those injected. Any of these side effects can last for a few hours up to 2 to 4 weeks and possibly longer.

In a very small number of individuals the injections may not work as completely as they do in others nor may they last as long as they do in others. Everyone responds to injections of BoNTA in their own way. Results also may vary depending on which BoNTA product is used. At times a touch-up injection 2 to 3 weeks later can improve the initial results.

You should inform the doctor if you develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing), or if any similar existing symptom worsens.

If loss of strength, muscle weakness, or impaired vision occurs, you should avoid driving a car or engaging in other potentially hazardous activities.

Adverse event information may be reported directly either to Allergan Inc. by phone to 800-433-8871, by facsimile to 714-246-5295 or by email to IR-Pharmacovigilance@allergan.com or to Medicis Aesthetics, Inc., by phone to 877-397-7671, depending on which product is used. In addition, adverse events may also be reported to the FDA MedWatch Reporting System by the following methods:

•Online at www.fda.gov/medwatch/report.htm

•Phone at 1-800-FDA-1088

•Facsimile at 1-800-FDA-0718, using the MedWatch Form 3500 (available at www.fda.gove/medwatch.getforms.htm)

•Mail, using the postage-paid MedWatch Form 3500 to: MedWatch, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787

PREGNANCY, NEUROLOGIC DISEASE, AND MEDICATIONS

I am aware that BoNTA is absolutely contraindicated in all pregnant women and must not be injected if I am not sure whether or not I am pregnant. If I am trying to conceive, BoNTA should not be injected for three months prior to conception. BoNTA should not be injected if I am breastfeeding or if I have any neurologic disease such as multiple sclerosis or myasthenia gravis. The effect of BoNTA may be potentiated by aminoglycoside antibiotics such as spectinomycin, tobramycin, neomycin, gentamycin, kanamycin, or amikacin. Please notify the doctor or nurse if you are currently on such medications.

I am not nursing nor am I aware I am pregnant nor do I have any significant neurologic disease. (_____) (initial)

Today’s treatment will be performed with (circle one used): BOTOX® Cosmetic (onabotulinumtoxinA) or Dysport™ (abobotulinumtoxinA) or (Name of other product): _______________.

PHOTOGRAPHS

I authorize the taking of photographs and videos and their use for scientific and medical purposes both in publications and presentations. I understand that my identity will be protected.

PAYMENT

I understand this is a cosmetic procedure and payment is my responsibility and due at the time of treatment.

I have read and completely understand all of the above. All of my questions have been answered satisfactorily by the doctor and nurse. I accept the risks, benefits, and potential complications of this procedure and hereby give my informed consent to be treated with (circle one): BOTOX® Cosmetic (onabotulinumtoxinA) or DYSPORT™ (abobotulinumtoxinA) or (Name of other product): _______________.

Signed __________________________ Date ____________________

Name ___________________________ Witness _________________

TreatingPhysician: _________________________________________