Safety of Botulinum Toxin A in Aesthetic Treatments: A Systematic Review of Clinical Studies MAURIZIO CAVALLINI, MD,* PIERFRANCESCO CIRILLO, MD,† SALVATORE PIERO FUNDARO , MD,‡ SANDRO QUARTUCCI, MD,† CHANTAL SCIUTO, MD,† GIUSEPPE SITO, MD,§ DAVIDE TONINI, MD,¶ GLORIA TROCCHI, MD,† AND MASSIMO SIGNORINI, MD**
BACKGROUND The use of botulinum toxin A (BoNT-A) for aesthetic treatments is growing steadily, and new safety data have been reported in recently published studies. OBJECTIVE To investigate the safety data on the use of the three BoNT-A formulations approved for facial aesthetics from recent studies and to confirm their safety profiles. METHODS The literature search was conducted using three online databases restricted to the timeframe from January 2000 to June 2012. Only clinical trials, randomized or open label, with safety as the primary or secondary endpoint, were included. RESULTS Thirty-five papers were selected, with a total of subjects 8,787 studied. OnabotulinumtoxinA was used in 60.0% of the studies, abobotulinumtoxinA in 37.1%, and incobotulinumtoxinA in 2.8%. The glabella was the most investigated area (51.4%), followed by the upper face (25.7%), crow’s feet (11.4%), and lower face (11.4%). Treatment-related adverse events were blepharoptosis (2.5%), brow ptosis (3.1%), and eye sensory disorders (3%) in the upper face and lip asymmetries and imbalances in the lower face (6.9%). All of these events resolved spontaneously. CONCLUSION The short-term safety profile of BoNT-A in cosmetic nonsurgical procedures was confirmed for all the three commercial formulations. The authors have indicated no significant interest with commercial supporters.
T
he use of botulinum toxin A (BoNT-A) in medicine started in the early 1970s, when Dr. Alan Scott experimented with it to treat strabismus.1 After Food and Drug Administration (FDA) approval in 1989 for its use in the treatment of blepharospasm and hemifacial spasm, BoNT-A was also investigated for a wide spectrum of off-label therapeutic indications for various clinical disorders.2,3 Carruthers and Carruthers,4 using the neurotoxin for medical conditions in the periorbital region, later reported rhytid improvement in the areas of injection. BoNT-A was therefore introduced specifically for cosmetic treatments and received FDA approval for the treatment of glabellar rhytides
in 2002. After the first BoNT-A formulation (BOTOX; Allergan Inc., Irvine, CA) in 1979, two more products were introduced: Dysport (Ipsen Ltd, Slough, UK) in 1991 and Xeomin (Merz Pharmaceuticals GmbH, Frankfurt, Germany) in 2009. Advertisements constantly promote the importance of a young and attractive look and that our image is important to a successful and happy life. Literature shows that treatment of the glabellar region with BoNT-A may correlate with reduced negative moods and regulate psychological states.5,6 In a recent U.S. survey, over the last 15 years, the number of cosmetic nonsurgical procedures increased 356%.7
*Unit of Plastic Surgery, Centro Diagnostico Italiano, Milan, Italy; †Private practice, Rome, Italy; ‡Multimed, Bologna, Italy; §Seconda Universita` degli Studi di Napoli, Naples, Italy; ¶Private practice, Verona, Italy; **Istituto Dermatologico Europeo, Milan, Italy © 2014 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2014;40:525–536 DOI: 10.1111/dsu.12463 525
REVIEW OF BONT-A SAFETY IN FACIAL AESTHETICS
BoNT-A was the top procedure for women and men, with more than 4.0 million injections administered,7 although possibly because the drug is a toxin, the safety of BoNT-A in aesthetic treatments is one of the most frequent concerns that patients in our practice raise. This systematic review investigates, for each of the three BoNT-A formulations, the most recent safety data on the treatment of different facial areas. The aim is to confirm the safety profile of BoNT-A in cosmetic treatments.
Methods and Materials A literature search was conducted using three electronic sources (PubMed, Scopus, Science Direct) from January 2000 to June 2012. We selected January 2000 because we arbitrarily considered this to be when aesthetic treatments became more common after the pioneering studies of the 1990s. Only studies published in English and with the abstract available were included. The keywords used for paper searching included “onabotulinumtoxinA,” “abobotulinumtoxinA,” “incobotulinumtoxinA,” “Botox/Botox cosmetic/ Vistabel/Vistabex,” “Dysport/Azzalure/Reloxin),” “Xeomin/Bocouture,” AND “safety,” AND “aesthetic,” AND “cosmetic.” Specific inclusion and exclusion criteria for literature selection were previously established. Inclusion Criteria ● Clinical trials, randomized double-blind or openlabel (level I of evidence as defined by evidencebased medicine guidelines)8 ● Safety as a primary or secondary endpoint ● Indication of the BoNT-A formulation used, according to the FDA denomination9 (onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA) or to its commercial brand name.
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DERMATOLOGIC SURGERY
Exclusion Criteria ● Evaluation of the efficacy only of BoNT-A treatment in aesthetic or medical conditions ● Safety of BoNT-A in medical conditions ● Clinical trials in which the BoNT-A formulation used was not specified ● All other studies investigating safety but not classified as clinical trials, including abstracts, posters, news, case reports, consensus, metaanalyses, and opinions Clinical trials meeting the inclusion criteria were divided into four groups based on the area of treatment: glabellar lines, crow’s feet, upper face (forehead only or forehead, glabella, crow’s feet), and lower face.
Results Literature Search Fifty-seven clinical studies investigating the safety of BoNT-A in facial aesthetics were found. Of these, 31 were eligible to be included in our review. BoNT-A formulations were identified with their commercial brand names or with the FDA identification names. OnabotulinumtoxinA corresponds to Botox, Vistabel, and Vistabex (Allergan, Inc.), abobotulinumtoxinA to Dysport and Azzalure (Ipsen Ltd.), and incobotulinumtoxinA to Xeomin and Bocouture (Merz Pharmaceuticals Gmbh). Of all the studies included in our review, 21 (60.0%) examined the safety of onabotulinumtoxinA, 13 (37.1%) assessed abobotulinumtoxinA, and one (2.8%) examined incobotulinumtoxinA. Treatment of glabellar lines was the most investigated (51.4%), followed by upper face (25.7%), crow’s feet (11.4%), and lower face (11.4%). The total number of investigated patients was 8,787. The details of each study are reported in Tables 1–4 divided according to area of treatment. Information on the
CAVALLINI ET AL
doses of onabotulinumtoxinA administered was missing in one study,10 and in another publication, the follow-up period after abobotulinumtoxinA treatment was not reported.11 These papers were included in the review anyway. Safety Profile In all the included trials, adverse events (AEs) were reported for the treatment and placebo groups during the follow-up period and rated according to severity and relationship to the treatment. Severity was graded as mild (awareness but tolerable), moderate (interfering with normal activity), or severe (incapacitating). AEs were considered serious if they were life-threatening or resulted in death, hospitalization, or a persistent or significant disability or incapacity. The relationship to study treatment (none, possible, probable, definite) was defined based on the presence or absence of any other possible cause and the time interval between injection and AE observation. Glabellar lines The most frequently reported AEs were headache, bruising, and respiratory tract infections (Table 1), but their incidence was not statistically significantly different between treated and placebo groups in any of the studies.
moderate) in 203 patients (5.4%) lasting 20 (mild) or 40 (moderate) days, although in subsequent studies with onabotulinumtoxinA and abobotulinumtoxinA, the rate of blepharoptosis was lower.18,20,22,27 For example, in a multicenter double-blind study with abobotulinumtoxinA followed by two to three cycles of open-label treatment, blepharoptosis developed in 10 of 311 treated patients (3.2%), with the incidence declining at each cycle.21 The total number of studied patients and of blepharoptosis cases reported in these studies are summarized in Tables 1 and 3. The average incidence of this AE was 2.5%. Eyebrow ptosis was another treatment-related AE, mostly reported after the upper third treatments, with an average incidence of 3.1%.10,11,17,33–38 All of these cases resolved completely, but duration of the AE was usually not specified. Eyebrow ptosis was also reported in one purely glabellar trial, with three affected patients (2.5%).15 All were mild and resolved completely: one in 2 days, one in 4 weeks, and one in 7 weeks.
Headache occurred in up to 16.8% of treated patients and 20% in the control groups.12–26 The events, usually mild to moderate, developed between a few hours and a few days after injection and resolved spontaneously. The duration was not specified.
Other treatment-related AEs reported after glabella or upper third treatment were eye sensory disorders, such as a sensation of heavy eyelids (BoNT-A 12%, placebo 2%) and an abnormal sensation in the eyes (BoNT-A 5.3%, placebo 0%) (Table 1).18,26 The average rate of these AEs was 3%. In a double-blind trial comparing two doses of abobotulinumtoxinA, “Spock” eyebrows in the treated patients were also observed, with a dose-related incidence.28 “Spock” eyebrows are related more to the position of injection than absolute dose. No eye disorders were reported after incobotulinumtoxinA injection in the only selected study with this formulation.25
Blepharoptosis was reported in onabotulinumtoxinA and abobotulinumtoxinA trials, with a variable incidence in the treated groups and no episodes in the placebo groups (Table 1).16–20,22–24,26,27 This AE is therefore definitely treatment related. An early double-blind study with onabotulinumtoxinA17 reported 12 episodes of blepharoptosis (8 mild, 4
Crow’s feet After onabotulinumtoxinA injection, mild bruising was observed in up to 25% of treated patients, with similar frequency in the placebo group (Table 2).29,30 Other AEs were headache and infections such as primary common cold, pharyngitis, and sinusitis (Table 2). However, their incidence
40:5:MAY 2014
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Treatment Schedule (Dose, U)
OnaBoNT-A (20)
OnaBoNT-A (20)
OnaBoNT-A (20)
OnaBoNT-A (10, 20)
OnaBoNT-A (20)
OnaBoNT-A (20) OnaBoNT-A (20)
OnaBoNT-A (RCT: 10, 20, 30, 40) (OL: 30)
OnaBoNT-A (10,2)
AboBoNT-A (25, 50, 75)
Study
Carruthers 200217
Carruthers 200315
Fagien 200712
DERMATOLOGIC SURGERY
Harii 200827
Wu 200918
Dailey 201150 Stotland 200713
Carruthers 200515
Kawashima 200926
Asher 200414
102 BoNT-A (1:1:1) 17 placebo
363 BoNT-A (1:1)
RCT: 80 BoNT-A, of which 50% OL enrolled
45 BoNT-A 58 BoNT-A
34 BoNT-A 31 placebo 91 BoNT-A (1:1) 49 placebo 170 BoNT-A 57 placebo
202 BoNT-A 71 placebo
203 BoNT-A 61 placebo
Number of Participants
18–70
20–64
18–65
30–50 35–60
18–65
20–64
30–54
18–75
18–75
Age
6 months
64 weeks
1 year + 1 year
26 months 120 days
120 days
16 weeks
12 weeks
120 days
120 days
Follow-Up
TABLE 1. Treatment with Botulinum Toxin A (BoNT-A) Formulations for Glabellar Lines
Blepharoptosis (2.2% vs 0.0%), heavy eyelids (12.1% vs 2%) Headache (8.8% vs 1.7%), abnormal sensation in eye (5.3% vs 0.0%), ptosis (0.6% vs 0%), nasopharyngitis (1.8% vs 0%), diarrhea (1.2% vs 0%), site pain (1.2% vs 0%), somnolence (1.2% vs 0%), influenza (1.2% vs 0%), eyelid edema (1.8% vs 0%), swollen face (1.8% vs 0%) None Headache (12%), soreness or itching at injection site (5%), pressure (2%) Headache (RCT, 11.2%; OL, 7.5%), migraine and tension of forehead (1.2% each), eyebrow ptosis (2.5% in both trials), pain upper nose (1.2%), tension above eyes (OL, 5.0%), tension upper nose (OL, 2.5%) Abnormal sensation in eye (6.7–11.5%), headache (4.9–7.2%), blepharoptosis (3.3–4.4%), pruritus (2.7–4.4%), discomfort (2.2–4.4%), pain (1.1–4.4%) Headache, migraine, vertigo, forehead rigidity, forehead muscle spasm (25 and 50 U, 2.9% each vs 0% placebo), forehead ecchymosis (50 U, 2.9% vs 5.9%); no adverse events in BoNT-A 75 U
Headache (15.3% vs 15.0%), respiratory tract infection (4.9% vs 8.3%), blepharoptosis (5.4% vs 0.0%), back pain (1.5% vs 5.0%), acne (1.0% vs 5.0%) Headache (11.4% vs 20.0%), blepharoptosis (1.0% vs 0.0%), erythema (3.0% vs 2.9%), edema (0.5% vs 4.3%), nausea (2.5% vs 2.9%), dizziness (1.5% vs 2.9%), pain (2.0% vs 1.4%), paresthesia (2.0% vs 1.4%), infection (2.0% vs 0%) Bruising in injection area in one patient
Adverse Events (%BoNT-A or %BoNT-A vs % placebo)
REVIEW OF BONT-A SAFETY IN FACIAL AESTHETICS
AboBoNT-A (50)
AboBoNT-A (50 fixed or 50, 60, 70, 80 variable dose; based on muscle mass)
AboBoNT-A (50)
AboBoNT-A (50, 60, 70) (women) (60, 70, 80) (men) AboBoNT-A (50)
AboBoNT-A (20, 50, 75)
AboBoNT-A (30, 50)
IncoBoNT-A (20)
Brandt 200919
Cohen 200920
Rubin 200921
Kane 200923
Monheit 200722
Rzany 200628
Imhof 201125
BoNT-A placebo BoNT-A placebo
105 BoNT-A
279 94 146 75
1200 BoNT-A
544 BoNT-A 272 placebo
311 BoNT-A 155 placebo
1,415 BoNT-A
105 BoNT-A 53 placebo
Number of Participants
18–65
18–75
20–76
18–65
20–80
84 days
16 weeks
120 days
13 months
150 days
23 months
24 months
≤65, 93% >65, 7%
21–74
180 days
Follow-Up
19–75
Age
Injection site events (18%); nervous system disorders (14%), of which headache (12%); ocular events (9%), of which ptosis (4%) Headache (16.8% vs 10.6%), nasopharyngitis (8.6% vs 8.5%), ptosis (0.8%) 30 U: Hypoesthesia, injection site discomfort, subjectively heavy eyelids, Spock eyebrow (BoNT-A, 4.1%), headache and pyrexia (placebo, 5.4%) 50 U: headache and Spock eyebrow (BoNT-A, 11%), eyelid ptosis (BoNT-A, 1.4%) headache, dizziness, blepharochalasis, swollen face (placebo, 10.5%) Nervous system disorders (3.8%), of which headache (2.9%)
Headache (10% vs 8%), eye disorders (9% vs 8%) of which ptosis (3% vs 0%), blepharospasm (1% vs 4%), nasopharyngitis (11% vs 11%) Nasopharyngitis (12.1% fixed, 3.0% variable dose), headache (5.8% fixed, 4.2% variable dose), upper respiratory tract infection (5.7% fixed, 2.8% variable dose), sinusitis (6% fixed, 1.2% variable dose), ptosis (1% fixed, 2% variable dose), dry eye and eyelid edema (1% of patients) Nervous system disorders (17% vs 3%), headache (12% vs 3%), nasopharyngitis (10% vs 4%), eye disorders (7% vs 3%), sinusitis (4% vs
BACKGROUND The use of botulinum toxin A (BoNT-A) for aesthetic treatments is growing steadily, and new safety data have been reported in recently published studies. OBJECTIVE To investigate the safety data on the use of the three BoNT-A formulations approved for facial aesthetics from recent studies and to confirm their safety profiles. METHODS The literature search was conducted using three online databases restricted to the timeframe from January 2000 to June 2012. Only clinical trials, randomized or open label, with safety as the primary or secondary endpoint, were included. RESULTS Thirty-five papers were selected, with a total of subjects 8,787 studied. OnabotulinumtoxinA was used in 60.0% of the studies, abobotulinumtoxinA in 37.1%, and incobotulinumtoxinA in 2.8%. The glabella was the most investigated area (51.4%), followed by the upper face (25.7%), crow’s feet (11.4%), and lower face (11.4%). Treatment-related adverse events were blepharoptosis (2.5%), brow ptosis (3.1%), and eye sensory disorders (3%) in the upper face and lip asymmetries and imbalances in the lower face (6.9%). All of these events resolved spontaneously. CONCLUSION The short-term safety profile of BoNT-A in cosmetic nonsurgical procedures was confirmed for all the three commercial formulations. The authors have indicated no significant interest with commercial supporters.
T
he use of botulinum toxin A (BoNT-A) in medicine started in the early 1970s, when Dr. Alan Scott experimented with it to treat strabismus.1 After Food and Drug Administration (FDA) approval in 1989 for its use in the treatment of blepharospasm and hemifacial spasm, BoNT-A was also investigated for a wide spectrum of off-label therapeutic indications for various clinical disorders.2,3 Carruthers and Carruthers,4 using the neurotoxin for medical conditions in the periorbital region, later reported rhytid improvement in the areas of injection. BoNT-A was therefore introduced specifically for cosmetic treatments and received FDA approval for the treatment of glabellar rhytides
in 2002. After the first BoNT-A formulation (BOTOX; Allergan Inc., Irvine, CA) in 1979, two more products were introduced: Dysport (Ipsen Ltd, Slough, UK) in 1991 and Xeomin (Merz Pharmaceuticals GmbH, Frankfurt, Germany) in 2009. Advertisements constantly promote the importance of a young and attractive look and that our image is important to a successful and happy life. Literature shows that treatment of the glabellar region with BoNT-A may correlate with reduced negative moods and regulate psychological states.5,6 In a recent U.S. survey, over the last 15 years, the number of cosmetic nonsurgical procedures increased 356%.7
*Unit of Plastic Surgery, Centro Diagnostico Italiano, Milan, Italy; †Private practice, Rome, Italy; ‡Multimed, Bologna, Italy; §Seconda Universita` degli Studi di Napoli, Naples, Italy; ¶Private practice, Verona, Italy; **Istituto Dermatologico Europeo, Milan, Italy © 2014 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2014;40:525–536 DOI: 10.1111/dsu.12463 525
REVIEW OF BONT-A SAFETY IN FACIAL AESTHETICS
BoNT-A was the top procedure for women and men, with more than 4.0 million injections administered,7 although possibly because the drug is a toxin, the safety of BoNT-A in aesthetic treatments is one of the most frequent concerns that patients in our practice raise. This systematic review investigates, for each of the three BoNT-A formulations, the most recent safety data on the treatment of different facial areas. The aim is to confirm the safety profile of BoNT-A in cosmetic treatments.
Methods and Materials A literature search was conducted using three electronic sources (PubMed, Scopus, Science Direct) from January 2000 to June 2012. We selected January 2000 because we arbitrarily considered this to be when aesthetic treatments became more common after the pioneering studies of the 1990s. Only studies published in English and with the abstract available were included. The keywords used for paper searching included “onabotulinumtoxinA,” “abobotulinumtoxinA,” “incobotulinumtoxinA,” “Botox/Botox cosmetic/ Vistabel/Vistabex,” “Dysport/Azzalure/Reloxin),” “Xeomin/Bocouture,” AND “safety,” AND “aesthetic,” AND “cosmetic.” Specific inclusion and exclusion criteria for literature selection were previously established. Inclusion Criteria ● Clinical trials, randomized double-blind or openlabel (level I of evidence as defined by evidencebased medicine guidelines)8 ● Safety as a primary or secondary endpoint ● Indication of the BoNT-A formulation used, according to the FDA denomination9 (onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA) or to its commercial brand name.
526
DERMATOLOGIC SURGERY
Exclusion Criteria ● Evaluation of the efficacy only of BoNT-A treatment in aesthetic or medical conditions ● Safety of BoNT-A in medical conditions ● Clinical trials in which the BoNT-A formulation used was not specified ● All other studies investigating safety but not classified as clinical trials, including abstracts, posters, news, case reports, consensus, metaanalyses, and opinions Clinical trials meeting the inclusion criteria were divided into four groups based on the area of treatment: glabellar lines, crow’s feet, upper face (forehead only or forehead, glabella, crow’s feet), and lower face.
Results Literature Search Fifty-seven clinical studies investigating the safety of BoNT-A in facial aesthetics were found. Of these, 31 were eligible to be included in our review. BoNT-A formulations were identified with their commercial brand names or with the FDA identification names. OnabotulinumtoxinA corresponds to Botox, Vistabel, and Vistabex (Allergan, Inc.), abobotulinumtoxinA to Dysport and Azzalure (Ipsen Ltd.), and incobotulinumtoxinA to Xeomin and Bocouture (Merz Pharmaceuticals Gmbh). Of all the studies included in our review, 21 (60.0%) examined the safety of onabotulinumtoxinA, 13 (37.1%) assessed abobotulinumtoxinA, and one (2.8%) examined incobotulinumtoxinA. Treatment of glabellar lines was the most investigated (51.4%), followed by upper face (25.7%), crow’s feet (11.4%), and lower face (11.4%). The total number of investigated patients was 8,787. The details of each study are reported in Tables 1–4 divided according to area of treatment. Information on the
CAVALLINI ET AL
doses of onabotulinumtoxinA administered was missing in one study,10 and in another publication, the follow-up period after abobotulinumtoxinA treatment was not reported.11 These papers were included in the review anyway. Safety Profile In all the included trials, adverse events (AEs) were reported for the treatment and placebo groups during the follow-up period and rated according to severity and relationship to the treatment. Severity was graded as mild (awareness but tolerable), moderate (interfering with normal activity), or severe (incapacitating). AEs were considered serious if they were life-threatening or resulted in death, hospitalization, or a persistent or significant disability or incapacity. The relationship to study treatment (none, possible, probable, definite) was defined based on the presence or absence of any other possible cause and the time interval between injection and AE observation. Glabellar lines The most frequently reported AEs were headache, bruising, and respiratory tract infections (Table 1), but their incidence was not statistically significantly different between treated and placebo groups in any of the studies.
moderate) in 203 patients (5.4%) lasting 20 (mild) or 40 (moderate) days, although in subsequent studies with onabotulinumtoxinA and abobotulinumtoxinA, the rate of blepharoptosis was lower.18,20,22,27 For example, in a multicenter double-blind study with abobotulinumtoxinA followed by two to three cycles of open-label treatment, blepharoptosis developed in 10 of 311 treated patients (3.2%), with the incidence declining at each cycle.21 The total number of studied patients and of blepharoptosis cases reported in these studies are summarized in Tables 1 and 3. The average incidence of this AE was 2.5%. Eyebrow ptosis was another treatment-related AE, mostly reported after the upper third treatments, with an average incidence of 3.1%.10,11,17,33–38 All of these cases resolved completely, but duration of the AE was usually not specified. Eyebrow ptosis was also reported in one purely glabellar trial, with three affected patients (2.5%).15 All were mild and resolved completely: one in 2 days, one in 4 weeks, and one in 7 weeks.
Headache occurred in up to 16.8% of treated patients and 20% in the control groups.12–26 The events, usually mild to moderate, developed between a few hours and a few days after injection and resolved spontaneously. The duration was not specified.
Other treatment-related AEs reported after glabella or upper third treatment were eye sensory disorders, such as a sensation of heavy eyelids (BoNT-A 12%, placebo 2%) and an abnormal sensation in the eyes (BoNT-A 5.3%, placebo 0%) (Table 1).18,26 The average rate of these AEs was 3%. In a double-blind trial comparing two doses of abobotulinumtoxinA, “Spock” eyebrows in the treated patients were also observed, with a dose-related incidence.28 “Spock” eyebrows are related more to the position of injection than absolute dose. No eye disorders were reported after incobotulinumtoxinA injection in the only selected study with this formulation.25
Blepharoptosis was reported in onabotulinumtoxinA and abobotulinumtoxinA trials, with a variable incidence in the treated groups and no episodes in the placebo groups (Table 1).16–20,22–24,26,27 This AE is therefore definitely treatment related. An early double-blind study with onabotulinumtoxinA17 reported 12 episodes of blepharoptosis (8 mild, 4
Crow’s feet After onabotulinumtoxinA injection, mild bruising was observed in up to 25% of treated patients, with similar frequency in the placebo group (Table 2).29,30 Other AEs were headache and infections such as primary common cold, pharyngitis, and sinusitis (Table 2). However, their incidence
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Treatment Schedule (Dose, U)
OnaBoNT-A (20)
OnaBoNT-A (20)
OnaBoNT-A (20)
OnaBoNT-A (10, 20)
OnaBoNT-A (20)
OnaBoNT-A (20) OnaBoNT-A (20)
OnaBoNT-A (RCT: 10, 20, 30, 40) (OL: 30)
OnaBoNT-A (10,2)
AboBoNT-A (25, 50, 75)
Study
Carruthers 200217
Carruthers 200315
Fagien 200712
DERMATOLOGIC SURGERY
Harii 200827
Wu 200918
Dailey 201150 Stotland 200713
Carruthers 200515
Kawashima 200926
Asher 200414
102 BoNT-A (1:1:1) 17 placebo
363 BoNT-A (1:1)
RCT: 80 BoNT-A, of which 50% OL enrolled
45 BoNT-A 58 BoNT-A
34 BoNT-A 31 placebo 91 BoNT-A (1:1) 49 placebo 170 BoNT-A 57 placebo
202 BoNT-A 71 placebo
203 BoNT-A 61 placebo
Number of Participants
18–70
20–64
18–65
30–50 35–60
18–65
20–64
30–54
18–75
18–75
Age
6 months
64 weeks
1 year + 1 year
26 months 120 days
120 days
16 weeks
12 weeks
120 days
120 days
Follow-Up
TABLE 1. Treatment with Botulinum Toxin A (BoNT-A) Formulations for Glabellar Lines
Blepharoptosis (2.2% vs 0.0%), heavy eyelids (12.1% vs 2%) Headache (8.8% vs 1.7%), abnormal sensation in eye (5.3% vs 0.0%), ptosis (0.6% vs 0%), nasopharyngitis (1.8% vs 0%), diarrhea (1.2% vs 0%), site pain (1.2% vs 0%), somnolence (1.2% vs 0%), influenza (1.2% vs 0%), eyelid edema (1.8% vs 0%), swollen face (1.8% vs 0%) None Headache (12%), soreness or itching at injection site (5%), pressure (2%) Headache (RCT, 11.2%; OL, 7.5%), migraine and tension of forehead (1.2% each), eyebrow ptosis (2.5% in both trials), pain upper nose (1.2%), tension above eyes (OL, 5.0%), tension upper nose (OL, 2.5%) Abnormal sensation in eye (6.7–11.5%), headache (4.9–7.2%), blepharoptosis (3.3–4.4%), pruritus (2.7–4.4%), discomfort (2.2–4.4%), pain (1.1–4.4%) Headache, migraine, vertigo, forehead rigidity, forehead muscle spasm (25 and 50 U, 2.9% each vs 0% placebo), forehead ecchymosis (50 U, 2.9% vs 5.9%); no adverse events in BoNT-A 75 U
Headache (15.3% vs 15.0%), respiratory tract infection (4.9% vs 8.3%), blepharoptosis (5.4% vs 0.0%), back pain (1.5% vs 5.0%), acne (1.0% vs 5.0%) Headache (11.4% vs 20.0%), blepharoptosis (1.0% vs 0.0%), erythema (3.0% vs 2.9%), edema (0.5% vs 4.3%), nausea (2.5% vs 2.9%), dizziness (1.5% vs 2.9%), pain (2.0% vs 1.4%), paresthesia (2.0% vs 1.4%), infection (2.0% vs 0%) Bruising in injection area in one patient
Adverse Events (%BoNT-A or %BoNT-A vs % placebo)
REVIEW OF BONT-A SAFETY IN FACIAL AESTHETICS
AboBoNT-A (50)
AboBoNT-A (50 fixed or 50, 60, 70, 80 variable dose; based on muscle mass)
AboBoNT-A (50)
AboBoNT-A (50, 60, 70) (women) (60, 70, 80) (men) AboBoNT-A (50)
AboBoNT-A (20, 50, 75)
AboBoNT-A (30, 50)
IncoBoNT-A (20)
Brandt 200919
Cohen 200920
Rubin 200921
Kane 200923
Monheit 200722
Rzany 200628
Imhof 201125
BoNT-A placebo BoNT-A placebo
105 BoNT-A
279 94 146 75
1200 BoNT-A
544 BoNT-A 272 placebo
311 BoNT-A 155 placebo
1,415 BoNT-A
105 BoNT-A 53 placebo
Number of Participants
18–65
18–75
20–76
18–65
20–80
84 days
16 weeks
120 days
13 months
150 days
23 months
24 months
≤65, 93% >65, 7%
21–74
180 days
Follow-Up
19–75
Age
Injection site events (18%); nervous system disorders (14%), of which headache (12%); ocular events (9%), of which ptosis (4%) Headache (16.8% vs 10.6%), nasopharyngitis (8.6% vs 8.5%), ptosis (0.8%) 30 U: Hypoesthesia, injection site discomfort, subjectively heavy eyelids, Spock eyebrow (BoNT-A, 4.1%), headache and pyrexia (placebo, 5.4%) 50 U: headache and Spock eyebrow (BoNT-A, 11%), eyelid ptosis (BoNT-A, 1.4%) headache, dizziness, blepharochalasis, swollen face (placebo, 10.5%) Nervous system disorders (3.8%), of which headache (2.9%)
Headache (10% vs 8%), eye disorders (9% vs 8%) of which ptosis (3% vs 0%), blepharospasm (1% vs 4%), nasopharyngitis (11% vs 11%) Nasopharyngitis (12.1% fixed, 3.0% variable dose), headache (5.8% fixed, 4.2% variable dose), upper respiratory tract infection (5.7% fixed, 2.8% variable dose), sinusitis (6% fixed, 1.2% variable dose), ptosis (1% fixed, 2% variable dose), dry eye and eyelid edema (1% of patients) Nervous system disorders (17% vs 3%), headache (12% vs 3%), nasopharyngitis (10% vs 4%), eye disorders (7% vs 3%), sinusitis (4% vs
