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A Review of OnabotulinumtoxinA (Botox)

Z. Paul Lorenc, Jeffrey M. Kenkel, Steven Fagien, Haideh Hirmand, Mark S. Nestor, Anthony P. Sclafani, Jonathan M. Sykes and
Heidi A. Waldorf
Aesthetic Surgery Journal 2013 33: 9S
DOI: 10.1177/1090820X12474629

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 Supplemental Article
A Review of OnabotulinumtoxinA (Botox)
Z. Paul Lorenc, MD; Jeffrey M. Kenkel, MD; Steven Fagien, MD;
Haideh Hirmand, MD; Mark S. Nestor, MD, PhD;
Anthony P. Sclafani, MD; Jonathan M. Sykes, MD; and
Heidi A. Waldorf, MD
Abstract
OnabotulinumtoxinA was introduced to the US market in 2002 as the first botulinum toxin type A (BoNTA) approved for facial aesthetics. This article
provides an overview of onabotulinumtoxinA’s uses and indications as well as safety and efficacy data. As with other BoNTA products, onabotulinumtoxinA
is generally well tolerated. Consideration is also given to clinical applications of the product. Information on handling, storage, and dosing is provided.
Keywords
facial aesthetics, glabellar lines, neuromodulators, neurotoxins, Botox, onabotulinumtoxinA, Dysport, abobotulinumtoxinA, botulinum neurotoxin type A
Accepted for publication March 16, 2012.
Injection of botulinum toxin type A (BoNTA) for the aes-
thetic correction of glabellar lines and other facial enhance-
ments is the most common cosmetic procedure in the
United States.1 In 2010, more than 2.4 million BoNTA proce-
dures were performed, according to statistics from the
American Society for Aesthetic Plastic Surgery.2 As the first
BoNTA product available in the United States, onabotuli-
numtoxinA (Botox; Allergan, Irvine, California; Vistabel
outside of the United States) was approved by the US Food
and Drug Administration (FDA) in 2002 for aesthetic appli-
cations. It is officially indicated for the temporary improve-
ment in the appearance of moderate to severe glabellar lines
associated with corrugator and/or procerus muscle activity
in adults 65 years and younger,3 although it is also used
widely in an off-label fashion for horizontal forehead lines,
“crow’s feet,” and many other areas. This review article
summarizes key efficacy and safety studies. Consideration
is given to variable dosing strategies, and a discussion sum-
marizes practical considerations related to onabotulinum-
toxinA, including product handling.
Efficacy
In 2002 and 2003, articles were published reporting on a
total of 537 patients who were enrolled in 2 phase 3, ran-
domized, multicenter, double-blind, placebo-controlled
studies of identical design to evaluate the efficacy and
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Aesthetic Surgery Journal
33(1S) 9­S–12S
© 2013 The American Society for
Aesthetic Plastic Surgery, Inc.
Reprints and permission:
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DOI: 10.1177/1090820X12474629
www.aestheticsurgeryjournal.com
safety of onabotulinumtoxinA for temporary improvement
of the appearance of moderate to severe glabellar facial
lines. Of those enrolled, 405 patients received onabotuli-
numtoxinA and 132 patients received placebo. For patients
receiving onabotulinumtoxinA, total dosage was 20 U,
equally divided into 5 injection points.4,5 Glabellar line
severity was evaluated at maximum frown on day 30 by
Dr Lorenc is a plastic surgeon in private practice in New York, New
York. Dr Kenkel is Professor and Vice Chairman of the Department
of Plastic Surgery at the University of Texas Southwestern Medical
Center at Dallas in Dallas, Texas, and Associate Editor of Aesthetic
Surgery Journal. Dr Fagien is a plastic surgeon in private practice
in Boca Raton, Florida. Dr Hirmand is Assistant Clinical Professor
at Weill-Cornell Medical College, New York, New York. Dr Nestor
is Voluntary Associate Professor in the Department of Dermatology
and Cutaneous Surgery at the University of Miami Miller School of
Medicine, Miami, Florida. Dr Sclafani is Director of Facial Plastic
Surgery and Professor of Otolaryngology–Head and Neck Surgery,
Facial Plastic Surgery, at The New York Eye and Ear Infirmary,
New York, New York. Dr Sykes is Director of Facial Plastic and
Reconstructive Surgery, UC Davis Medical Center, Sacramento,
California. Dr Waldorf is Associate Clinical Professor of Dermatology
at Mount Sinai School of Medicine, New York, New York.
Corresponding Authors:
Dr Z. Paul Lorenc, 983 Park Ave, New York, NY 10028, USA.
E-mail: lorenc@lorenc.com
10S Aesthetic Surgery Journal 33(1S)
the investigators’ assessment and the subjects’ global
assessment of change. A validated 4-point grading scale
(0 = none, 3 = severe) was used by the investigators. The
patients’ global assessment of change was rated on a scale
of +4 (complete improvement) to –4 (very marked wors-
ening). Responders were defined as those having a grade
of at least +2 (moderate improvement); these patients
would have had an initial severity grade of 0 or 1.
Patients in the onabotulinumtoxinA group experienced
significantly greater improvement in glabellar line severity
than patients in the placebo group in both investigator and
patient assessments. By investigator assessment, 80% of
patients receiving onabotulinumtoxinA were considered
responders versus 3% of those receiving placebo at the pri-
mary efficacy time point of day 30 (P < .001). By patient
assessment of change, 89% in the onabotulinumtoxinA
group were responders vs 7% in the placebo group (P <
.001).4,5
The studies also evaluated the efficacy of onabotulinum-
toxinA versus placebo in patients older than 65 years; a total
of 32 patients (6%) in the studies fell into this group. Among
these patients, there was a lower treatment-associated response
compared with those patients younger than 65 years. Using
investigators’ assessments, only 39% of older patients in the
onabotulinumtoxinA group (vs 22% placebo) were respond-
ers, although, by patient assessment, 70% were responders
(vs 11% placebo).4,5 This age-related discrepancy is multifac-
torial, encompassing elements such as the degree of skin’s
intrinsic elasticity and the patient’s muscle mass.
Onset and Duration of Effect
Onset of onabotulinumtoxinA occurs within 7 days. In the
2 clinical trials previously described, the degree of response
by both investigator and patient assessment was similar at
day 7 and day 30.4,5 Peak effect was observed at day 30 in
both studies. The studies were not designed to test spe-
cifically for duration of effect, but the results did suggest
that onabotulinumtoxinA’s duration in treatment of glabel-
lar lines is similar to the 3 to 6 months reported for other
indications.6 Other studies of onabotulinumtoxinA for
treatment of glabellar lines suggest injection intervals of as
long as 3 to 7 months.7-10 Durations longer than 4 months,
however, are more typical of patients who have received a
series of treatments over the course of at least 1 year and
may be dose dependent.4
Variable Dosing
Because of variations in the size and strength of glabellar
complex muscles, a range of dosages can be administered to
achieve optimal effect. A variable dosing study has been
published that evaluated doses of 20, 40, 60, or 80 U for treat-
ment of glabellar lines in men.11 Higher doses were found to
be safe and effective and, in many cases, more effective than
20 U for those patients with strong glabellar features. Many
clinicians today start with dosages of 15 to 20 U and then
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administer higher dosages depending on the muscle mass
and/or sex of the patient. Note that common dosages for off-
label applications such as crow’s feet are covered in the
consensus article found elsewhere in this supplement.
Long-Term Safety
As with other BoNTA products, onabotulinumtoxinA is
generally well tolerated. The most frequent adverse events
reported by more than 5% of patients in clinical trials
included headache, respiratory tract infection, blepharop-
tosis, back pain, and acne. A significant adverse event for
any BoNTA product is ptosis, which can manifest as either
brow or eyelid ptosis (blepharoptosis). In an early clinical
trial, blepharoptosis was reported in 5.4% of patients.
Studies of the second BoNTA product (Dysport; Medicis
Aesthetics, Scottsdale, Arizona) suggest that rates of ptosis
generally decrease with increased clinician experience.2
The long-term safety of onabotulinumtoxinA after repeat
administrations has been established based on years of
clinical experience as well as a meta-analysis of the number
and frequency of adverse events from 36 studies involving
2309 subjects.12 No study reported any serious adverse
events. Focal weakness was the only adverse event to occur
more often among the onabotulinumtoxinA group com-
pared with the control group. Long-term onabotulinumtox-
inA administration has been assessed in various treatment
settings, with the level and duration of onabotulinumtoxinA
efficacy response being maintained over repeated rounds of
injection with no major safety concerns.13
Discussion: Onabotulinumtoxin-a
in Clinical Practice
Product labeling advises that each BoNTA product is
unique and its unit of measure is not interchangeable;
formulations of each BoNTA product differ from one
another, mostly based on the proprietary manufacturing
process unique to each product. However, many physi-
cians attempt to describe relative differences in the unit
ratios of the different approved toxins. Caution must
always be exercised to ensure appropriate dosing.
A box warning on the onabotulinumtoxinA package
insert and on the inserts of the 2 other BoNTA products
available in the United States alerts physicians to potential
for distant spread of toxin beyond the injection site. Spread
of onabotulinumtoxinA is dependent on the volume injected
and the injection technique, with higher volume of product
leading to increased physical distribution as the fluid is
pushed from the injection point through the tissues.14
Handling and Preparation
OnabotulinumtoxinA and diluent do not contain preserva-
tives. Once opened and reconstituted, the product should be
refrigerated at 2°C  to  8°C (36°F  to  46°F). OnabotulinumtoxinA
Lorenc et al 11S
is supplied in single-use vials of 50 U and 100 U. Dilution
with 1.25 mL 0.9% sterile, preservative-free saline (for the
50-U vial) into a syringe to obtain a reconstituted solution
at a concentration of 4 U/0.1 mL is recommended by
the package insert, with a total treatment dose of 20 U in
0.5 mL. Product labeling advises that, once opened, any
remaining solution should be discarded. Many clinicians, in
an off-label fashion, do use a reconstituted vial more than
once, provided that the same needle and syringe is not rein-
serted into the vial.2 This recommendation, however, is
beyond the scope of official product labeling, and not all
clinicians are in agreement because the product does not
contain any antimicrobial agent.
OnabotulinumtoxinA With Other Aesthetic
Procedures
BoNTA products may be used in conjunction with other
aesthetic procedures, such as injectable dermal fillers and
volumizing agents. There is no consensus about the order
in which the two should be injected or whether the injec-
tions should be performed on the same day.2 However,
there may be practical reasons for separating injections. A
patient injected with BoNTA on one visit may return after
approximately 1 week and be satisfied with the neuro-
modulator effect alone, deciding to forego administration
of the dermal filler.
Combination therapy with neuromodulators and fillers/
volumizing agents for facial rejuvenation has been a wide-
spread practice for close to a decade. However, until
recently, systematic studies of BoNTA therapy in combina-
tion with hyaluronic acid (HA) for use in the lower face
had not been conducted. Carruthers and colleagues15
evaluated the safety and efficacy of combination treatment
using onabotulinumtoxinA with a 24-mg/mL smooth,
cohesive HA gel filler. Patients treated with onabotulinum-
toxinA plus HA had greater improvement from baseline
than subjects treated with either onabotulinumtoxinA
alone or HA alone by both investigator and patient assess-
ments.15,16 The authors concluded that combination ther-
apy is superior to either modality used alone to rejuvenate
the lower face. These findings support what has been
routinely observed in clinical practice.
OnabotulinumtoxinA for Treatment of
Glabellar Lines in Repose
Although the efficacy of BoNTA has been established for
the treatment of glabellar frown lines, its effect for lines at
repose are less clear. To assess the effect of onabotulinum-
toxinA on the elimination of mild lines at rest, Carruthers
and colleagues17 analyzed 183 participants with mild lines
at repose who received 20 U of onabotulinumtoxinA and
64 participants, also with mild lines at repose, who
received placebo. These participants were evaluated at
days 7, 30, 60, 90, and 120. Compared with placebo, the
patients treated with onabotulinumtoxinA were more
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likely to have their lines at repose eliminated for each
point of evaluation. The highest response rate was
observed at day 30 (68%).17
On the basis of clinical experience and this study, the
supplement authors believe that these results can be
extrapolated to the other 2 BoNTA products and that
patients most likely to benefit from BoNTA treatment of
lines at rest are younger than 50 years, with mild lines at
repose. Patients with more severe wrinkle rating will likely
require a combination of approaches, including adminis-
tration of BoNTA, dermal filler/volumizing agents, resur-
facing procedures, and possibly surgical intervention.
Conclusions
The treatment of facial lines with onabotulinumtoxinA is
effective and well tolerated with a safety profile compara-
ble to placebo. Adverse events were mild or moderate in
clinical trials. Variable dosing based on sex and muscle
mass resulted in improved efficacy in many patients and
did not increase the risk of adverse events.
Acknowledgments
The authors acknowledge the editorial and writing assistance
of Mark R. Vogel, MA, a medical communications specialist in
San Francisco.
Disclosures
Dr Lorenc is a paid consultant for Mentor, Merz Aesthetics, Medi-
cis, and Johnson & Johnson. Dr Fagien is an advisory board
member and paid investigator for Allergan, Medicis, Merz Aes-
thetics, and Galderma. Dr Hirmand is a speaker for Medicis
Aesthetics, an advisory board member for Merz Aesthetics, and
a paid investigator for Invasix. Dr Nestor is an advisory board
member for Medicis, Merz Aesthetics, Galderma, Compulink,
and Allergan. Dr Sclafani is a paid consultant and grant recipient
for Aesthetic Factors. Dr Sykes is an advisory board member for
Mentor and Allergan and a member of the speakers bureau for
Sanofi-Aventis and Medicis. Dr Waldorf is an advisory board
member, paid consultant, and speakers bureau member for Merz
Aesthetics, Medicis, Allergan, Valeant, Solta, Bropelle, P&G,
Johnson & Johnson, Unilever, and Rhythera. Unless otherwise
noted, the faculty and planners have nothing to disclose. Edito-
rial and writing assistance for this manuscript was provided by
Medical Education Advocates.
Funding
This supplement was funded by an unrestricted educational
grant from Merz Aesthetics, the maker of one of the products
discussed in these articles.
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