Abstract
Background
Since its discovery as a facial aesthetic treatment >30 years ago, onabotulinumtoxinA has received worldwide approval for dynamic upper facial line treatment.
Objective
Meta-analysis examining the safety of onabotulinumtoxinA for treatment of glabellar lines (GL), crow’s feet lines (CFL), and forehead lines (FHL).
Methods
Participants (N = 5298) with moderate to severe GL, CFL, or FHL at maximum contraction received onabotulinumtoxinA or placebo in 1 of 18 registration studies (14 double-blind, placebo-controlled [DBPC]; 1 double-blind; 3 open-label). Adverse events (AEs) were analyzed by descriptive statistics and fixed-effects meta-analysis.
Results
In the overall double-blind placebo-controlled (DBPC) population, AEs were reported in 1443 (42.1%) and 486 (35.8%) participants in the onabotulinumtoxinA (n = 3431) and placebo (n = 1359) groups, respectively. Serious AEs were reported in 54 (1.6%) and 17 (1.3%) participants; 1 (spontaneous abortion) was considered possibly treatment related by the investigator. Using fixed-effects statistical meta-analysis, AEs of interest that were found to be statistically higher for onabotulinumtoxinA than placebo in the DBPC population were eyelid ptosis, eyelid sensory disorder, skin tightness, brow ptosis, eyelid edema, and facial pain (P ≤ .05).
Limitations
Retrospective, ad hoc analysis.
Conclusion
This meta-analysis confirms the onabotulinumtoxinA safety profile for GL, CFL, and FHL treatment, with no new onabotulinumtoxinA-associated AEs.
Key words: aesthetic, Botox, botulinum toxin, cosmetic, crow’s feet lines, forehead lines, glabellar lines, lateral canthal lines, onabotulinumtoxinA, rhytids
Capsule Summary.
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This update of a 2009 meta-analysis of the safety and tolerability of onabotulinumtoxinA more than triples the number of participants (N = 5298; 18 studies) and includes additional facial aesthetic indications.
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The onabotulinumtoxinA safety profile remained consistent with the product label, and no new signals emerged from the pooled populations.
Introduction
Over 30 years ago, onabotulinumtoxinA was found to have potential aesthetic applications in addition to its therapeutic indications.1, 2, 3, 4, 5 Since then, onabotulinumtoxinA efficacy and safety data from aesthetic indication clinical trials have been published in approximately 500 peer-reviewed journal articles.6 OnabotulinumtoxinA is now approved for upper facial lines, including glabellar lines (GL), crow’s feet lines (CFL), and forehead lines (FHL).6
A previous meta-analysis by Brin et al7 examined the safety and tolerability of onabotulinumtoxinA in more than 1600 participants treated for GL and CFL in 9 studies. Adverse events (AEs) associated with onabotulinumtoxinA were generally mild to moderate, and most treatment-related AEs were associated with local pharmacological effect or injection techniques.
This updated meta-analysis examines the onabotulinumtoxinA safety profile using data pooled from 18 studies in 5298 participants treated for GL, CFL, and FHL.
Methods
Study selection
Double-blind, placebo-controlled (DBPC), double-blind (DB), and open-label (OL) clinical studies of onabotulinumtoxinA for the treatment of GL, CFL, or FHL, and combinations thereof, were analyzed.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 These registration studies adhered to all regulatory guidelines for product licensure, and were conducted by Allergan (an AbbVie Company) or its business partners. All studies were completed, with databases locked and study reports available. All studies complied with the Declaration of Helsinki, included written informed consent, and were approved by an institutional review board (IRB).
Participants
Enrolled participants had investigator-rated moderate to severe, bilaterally symmetrical GL, CFL, or FHL at maximum contraction (frowning for GL; smiling for CFL; eyebrow elevation for FHL), based on Allergan’s validated facial wrinkle scales.
Assessments
Analyses were based on pooled safety populations overall (participants who received ≥1 injection of onabotulinumtoxinA or placebo) and by primary study treatment area (eg, GL, CFL, FHL). Demographic and disposition data were summarized by treatment group, while safety data were analyzed by treatment area, simultaneous treatment areas, and treatment cycle (as applicable). All AEs were classified by Medical Dictionary for Regulatory Activities, Version 21.1 (MedDRA) preferred terms (Table I) and were evaluated for possible distant spread of toxin (PDSOT) beyond the injection site. Subsequent to the present analysis, a preferred term, “Mephisto sign,” was introduced into MedDRA. Therefore, in this analysis, where appropriate, some instances of skin tightness were reassessed as a Mephisto sign.
Table I.
MedDRA preferred terms used to evaluate PDSOT
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MedDRA, Medical Dictionary for Regulatory Activities; PDSOT, possible distant spread of toxin.
Statistical analysis
AEs were coded using MedDRA 21.1 and summarized using descriptive statistics. A fixed-effects meta-analysis assumes that the studies being analyzed can be considered homogeneous; that is, they all share the same “effect size” (common odds ratio for AEs in this case) and can be combined to estimate it. This assumption can be tested by evaluating the level of heterogeneity among studies being combined. Study heterogeneity was assessed separately for each AE using the Q statistic and I2 index24; AEs with I2 ≤ 50% were considered homogeneous and could be combined.25 Incidence data for each homogeneous AE were fitted to fixed-effects meta-analytic models, using both the Peto method and Mantel–Haenszel method with continuity correction proportional to the reciprocal of the relative size of the opposite treatment group.26 AEs with high heterogeneity were not considered suitable to combine, and were evaluated descriptively by study. Comparisons between onabotulinumtoxinA and placebo were performed for treatment areas individually and collectively using the first 90 days of DBPC treatment cycle 1 to ensure comparable exposure across studies. Fisher's exact test was used to compare treatments for areas with only 1 DBPC study (FHL/GL/CFL simultaneously treated) or 2 DBPC studies with the same participants (CFL/GL simultaneously treated). All tests other than those for homogeneity were two-sided and conducted at the 0.05 significance level, with no adjustment for multiplicity as a conservative approach that was deemed appropriate for this safety analysis. SAS version 9.4 (SAS) was used for all statistical analyses.
Results
The analysis included 14 DBPC, 1 DB, and 3 OL registration studies (Table II): 9 studies from the previous meta-analysis (ie, 4 DBPC GL, 3 OL GL, and 2 DBPC CFL studies)7 and 9 additional studies (ie, 3 DBPC CFL, 2 DBPC CFL/GL, 1 DB CFL/GL, 2 DBPC FHL/GL, and 1 DBPC FHL/GL/CFL).14, 15, 16, 17, 18, 19, 20, 21,23 This report focuses on data pooled from the 14 DBPC studies (DBPC population).8, 9, 10,12,14, 15, 16, 17, 18, 19, 20, 21, 22, 23
Table II.
Study characteristics and number of participants included in meta-analysis of safety of onabotulinumtoxinA for upper facial lines
| Indication | Type of study (publication/study completion date) | Location | Dose/treatment, cycles | Duration, wk | DBPC population, n |
Total exposure population | |
|---|---|---|---|---|---|---|---|
| OnabotA | Placebo | ||||||
| GL | DBPC (2002)8 | North America | 20 U 1 cycle |
16 | 203 | 60 | 203 |
| DBPC (2003)27 | North America | 20 U 1 cycle |
16 | 202 | 70 | 202 | |
| OL (2004)11 | North America | 20 U 1 cycle |
16 | 0 | 0 | 96 | |
| OL/191622-907 (2001)7 | Japan | 20 U 1 cycle |
16 | 0 | 0 | 125 | |
| DBPC (2008)10 | Japan | 10 or 20 U 1 cycle |
16 | 90 | 49 | 90 | |
| OL (2009)13 | Japan | 10 or 20 U 1 cycle |
64 | 0 | 0 | 363 | |
| DBPC (2010)22 | China | 20 U 1 cycle |
16 | 170 | 57 | 190 | |
| CFL | DBPC (2005)12 | EU | 6-36 U 1 cycle |
24 | 130 | 32 | 130 |
| DBPC/191622-514 (2004)7 | EU | 12-36 U 1 cycle |
12 | 149 | 48 | 149 | |
| DBPC (2014)16,∗ | North America/EU | 24 U 1 cycle |
20 | 220 | 224 | 220 | |
| DBPC (2017)23,∗ | Japan | 12 U, 24 U Up to 5 cycles |
56 | 203 | 97 | 294 | |
| DBPC (2019)20,∗ | China | 24 U 1 cycle |
20 | 316 | 101 | 316 | |
| CFL and CFL/GL | DBPC (2015)14,∗ | North America/EU | CFL: 24 U GL: 20 U 2 cycles |
32 | 611 | 306 | 611 |
| DBPC (2015)15,∗,† | North America/EU | CFL: 24 U GL: 20 U 2 cycles |
20 | 100 | 0 | 100 | |
| CFL/GL | DB (2020)21,∗ | Japan | CFL: 12 U or 24 U + GL: 20 U Up to 5 cycles |
56 | 0 | 0 | 100 |
| FHL/GL | DBPC (2016)17,∗ DBPC (2017)18,∗ |
Canada North America/EU |
FHL: 10 U or 20 U + GL: 20 U 1 cycle FHL: 20 U + GL: 20 U Up to 3 cycles |
24 52 |
116 290 |
59 100 |
116 374 |
| FHL/GL and FHL/GL/CFL | DBPC (2018)19,∗ | North America/EU | FHL: 20 U + GL: 20 U or FHL: 20 U + GL: 20 U + CFL: 24 U Up to 3 cycles |
52 | 318 313 |
156 156 |
318 746 |
| Total | 3431 | 1359 | 4449 | ||||
CFL, Crow’s feet lines; CFL/GL, crow’s feet lines and glabellar lines combined; DBPC, double-blind placebo-controlled; EU, European Union; GL, glabellar lines; OL, open-label; OnabotA, onabotulinumtoxinA.
New studies relative to Brin et al.7
Extension of study 099, with 684 participants (onabotulinumtoxinA, n = 588 [including new exposure; n = 100]; placebo, n = 96).
Participants
Participants from 14 DBPC studies (N = 4690) were predominantly White (68.7%) or Asian (24.5%) and female (85.9%), with a median (range) age of 47.0 (18.0-85.0) years. Four DBPC studies were conducted in Asia (n = 1083) and 10 in North America/Europe (n = 3607). The total exposure population (N = 4449) was treated for GL only (n = 1269), CFL only (n = 1415), CFL/GL (n = 505), FHL/GL (n = 514), and FHL/GL/CFL (n = 746). Demographics were similar to those previously reported for the DBPC population (Table III).7
Table III.
Demographics by analysis population and treatment areas
| All DBPC |
GL DBPC |
CFL DBPC |
CFL + GL DBPC |
FHL + GL DBPC |
FHL + GL + CFL DBPC |
All OnabotA |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OnabotA (N = 3431) | Placebo (N = 1359) | OnabotA (N = 665) | Placebo (N = 236) | OnabotA (N = 1324) | Placebo (N = 808) | OnabotA (N = 405) | Placebo (N = 306) | OnabotA (N = 724) | Placebo (N = 315) | OnabotA (N = 313) | Placebo (N = 156) | (N = 4449) | |
| Age, y | |||||||||||||
| Median | 47.0 | 47.0 | 44.0 | 46.0 | 48.0 | 47.0 | 50.0 | 49.0 | 47.0 | 47.0 | 45.0 | 48.0 | 47.0 |
| Range | 18-85 | 22-74 | 22-78 | 22-69 | 22-75 | 22-74 | 24-85 | 25-73 | 18-77 | 22-73 | 21-76 | 22-73 | 18-85 |
| Sex, n (%) | |||||||||||||
| Female | 2953 (86.1) | 1163 (85.6) | 557 (83.8) | 203 (86.0) | 1131 (85.4) | 681 (84.3) | 355 (87.7) | 263 (85.9) | 626 (86.5) | 279 (88.6) | 284 (90.7) | 140 (89.7) | 3860 (86.8) |
| Male | 478 (13.9) | 196 (14.4) | 108 (16.2) | 33 (14.0) | 193 (14.6) | 127 (15.7) | 50 (12.3) | 43 (14.1) | 98 (13.5) | 36 (11.4) | 29 (9.3) | 16 (10.3) | 589 (13.2) |
| Race, n (%) | |||||||||||||
| White | 2379 (69.3) | 933 (68.7) | 341 (51.3) | 107 (45.3) | 740 (55.9) | 543 (67.2) | 358 (88.4) | 265 (86.6) | 655 (90.5) | 283 (89.8) | 285 (91.1) | 145 (92.9) | 2657 (59.7) |
| Asian | 822 (24.0) | 329 (24.2) | 269 (40.5) | 110 (46.6) | 529 (40.0) | 209 (25.9) | 6 (1.5) | 6 (2.0) | 16 (2.2) | 10 (3.2) | 2 (0.6) | 1 (0.6) | 1530 (34.4) |
| Black | 48 (1.4) | 24 (1.8) | 21 (3.2) | 7 (3.0) | 12 (0.9) | 10 (1.2) | 4 (1.0) | 2 (0.7) | 9 (1.2) | 7 (2.2) | 2 (0.6) | 3 (1.9) | 57 (1.3) |
| Other | 182 (5.3) | 73 (5.4) | 34 (5.1) | 12 (5.1) | 43 (3.2) | 46 (5.7) | 37 (9.1) | 33 (10.8) | 44 (6.1) | 15 (4.8) | 24 (7.7) | 7 (4.5) | 205 (4.6) |
CFL, Crow’s feet lines; DBPC, double-blind placebo-controlled; FHL, forehead lines; GL, glabellar lines; OnabotA, onabotulinumtoxinA.
Adverse events
Descriptive summary
AEs were reported in 42.1% and 35.8% of the onabotulinumtoxinA and placebo groups, respectively, and most commonly (≥2%) were headache, nasopharyngitis, injection site bruising, and upper respiratory tract infection (Table IV). In the onabotulinumtoxinA group, subjects reported the following: eyelid ptosis (1.1%; n = 38), eyelid sensory disorder (<1%; n = 26), eyelid edema (<1%; n = 12). Oral herpes, influenza, and injection site pain were numerically lower in incidence for the onabotulinumtoxinA group versus placebo.
Table IV.
Adverse events occurring in ≥1% of participants occurring across all treatment areas (DBPC population)
| Preferred term, n (%) | GL |
CFL |
CFL/GL |
FHL/GL |
FHL/GL/CFL |
All |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OnabotA N = 665 |
Placebo N = 236 |
OnabotA N = 1324 |
Placebo N = 808 |
OnabotA N = 405 |
Placebo N = 306 |
OnabotA N = 724 |
Placebo N = 315 |
OnabotA N = 313 |
Placebo N = 156 |
OnabotA N = 3431 |
Placebo N = 1359 |
|
| Overall | 300 (45.1) | 94 (39.8) | 483 (36.5) | 293 (36.3) | 210 (51.9) | 136 (44.4) | 312 (43.1) | 99 (31.4) | 138 (44.1) | 52 (33.3) | 1443 (42.1) | 486 (35.8) |
| Headache | 75 (11.3) | 27 (11.4) | 50 (3.8) | 31 (3.8) | 32 (7.9) | 21 (6.9) | 62 (8.6) | 17 (5.4) | 24 (7.7) | 8 (5.1) | 243 (7.1) | 75 (5.5) |
| Nasopharyngitis | 40 (6.0) | 14 (5.9) | 82 (6.2) | 44 (5.4) | 29 (7.2) | 20 (6.5) | 35 (4.8) | 10 (3.2) | 26 (8.3) | 5 (3.2) | 212 (6.2) | 68 (5.0) |
| Injection site bruising | 2 (0.3) | 2 (0.8) | 35 (2.6) | 16 (2.0) | 20 (4.9) | 6 (2.0) | 37 (5.1) | 8 (2.5) | 12 (3.8) | 5 (3.2) | 106 (3.1) | 26 (1.9) |
| Upper RTI | 4 (0.6) | 2 (0.8) | 29 (2.2) | 17 (2.1) | 16 (4.0) | 11 (3.6) | 14 (1.9) | 5 (1.6) | 5 (1.6) | 1 (0.6) | 68 (2.0) | 24 (1.8) |
| Injection site hematoma | 0 (0.0) | 0 (0.0) | 25 (1.9) | 8 (1.0) | 14 (3.5) | 4 (1.3) | 16 (2.2) | 3 (1.0) | 11 (3.5) | 3 (1.9) | 66 (1.9) | 11 (0.8) |
| Sinusitis | 8 (1.2) | 3 (1.3) | 14 (1.1) | 13 (1.6) | 10 (2.5) | 7 (2.3) | 15 (2.1) | 4 (1.3) | 6 (1.9) | 3 (1.9) | 53 (1.5) | 20 (1.5) |
| Influenza | 10 (1.5) | 1 (0.4) | 15 (1.1) | 11 (1.4) | 5 (1.2) | 5 (1.6) | 74 (1.0) | 5 (1.6) | 4 (1.3) | 4 (2.6) | 41 (1.2) | 17 (1.3) |
| Bronchitis | 6 (0.9) | 3 (1.3) | 16 (1.2) | 9 (1.1) | 10 (2.5) | 6 (2.0) | 6 (0.8) | 0 (0.0) | 2 (0.6) | 0 (0.0) | 40 (1.2) | 12 (0.9) |
| Eyelid ptosis | 16 (2.4) | 0 (0.0) | 0 (0.0) | 1 (0.1) | 5 (1.2) | 1 (0.3) | 15 (2.1) | 1 (0.3) | 2 (0.6) | 1 (0.6) | 38 (1.1) | 2 (0.1) |
| Oral herpes | 0 (0.0) | 1 (0.4) | 15 (1.1) | 8 (1.0) | 4 (1.0) | 3 (1.0) | 7 (1.0) | 6 (1.9) | 4 (1.3) | 6 (3.8) | 30 (0.9) | 15 (1.1) |
| Injection site pain | 16 (2.4) | 4 (1.7) | 4 (0.3) | 6 (0.7) | 3 (0.7) | 3 (1.0) | 5 (0.7) | 3 (1.0) | 0 (0.0) | 0 (0.0) | 28 (0.8) | 13 (1.0) |
Included only adverse events with incidence of ≥1% in either treatment group across all treatment areas in the DBPC population.
CFL, Crow’s feet lines; DBPC, double-blind placebo-controlled; FHL, forehead lines; GL, glabellar lines; OnabotA, onabotulinumtoxinA; RTI, respiratory tract infection.
Assessment of homogeneity
Across all treatment areas, 2 events, nasopharyngitis (GL; I2 = 51.46; P value associated with the Q statistic = 0.103) and upper respiratory tract infection (FHL/GL; I2 = 65.20; P = .056), had heterogeneity. Study-level treatment group incidence rates for nasopharyngitis varied, ranging from respective onabotulinumtoxinA and placebo incidence rates of 18.9% and 6.1% in 1 study to 3.0% and 6.7% in another study. Similarly, respective incidence rates for upper respiratory tract infection varied, ranging from 2.5% and 0.6% in 1 study to 0.3% and 3.0% in another study. The fixed modeling approach may not apply for these 2 events in these treatment areas as there was no consistent pattern related to onabotulinumtoxinA across the individual studies.
Fixed-effects statistical modeling
The meta-analysis statistical modeling method was applied to the DBPC population and GL, CFL, and FHL/GL treatment areas. Model-generated significant AEs were defined as those achieving P ≤ .05 using either the Peto or Mantel–Haenszel methodologies. Fisher’s exact tests were applied to the CFL/GL and FHL/GL/CFL treatment areas. The most common model-generated significant AEs for the DBPC population (all P < .04), regardless of treatment group, were eyelid ptosis, eyelid sensory disorder, skin tightness, brow ptosis, diarrhea, eyelid edema, facial pain, lower respiratory tract infection, pneumonia, rash, gastroesophageal reflux disease, periodontitis, and visual impairment (Table V). Considering the objective to describe the safety and tolerability of onabotulinumtoxinA, AEs favoring placebo were excluded following medical review. The remaining model-generated significant AEs (all P < .03) were eyelid ptosis, eyelid sensory disorder, skin tightness, brow ptosis, eyelid edema, and facial pain.
Table V.
Adverse events across all treatment areas, filtered by P ≤ .050 (DBPC population, treatment cycle 1, days 1-90)
| Preferred term, n (%) | OnabotA (N = 3431) | Placebo (N = 1359) | P value | Treatment group favored |
|---|---|---|---|---|
| Overall | 1136 (33.1) | 395 (29.1) | .0103 | OnabotA |
| Eyelid ptosis | 34 (1.0) | 1 (0.1) | .0024 | OnabotA |
| Eyelid sensory disorder | 25 (0.7) | 1 (0.1) | .0024 | OnabotA |
| Skin tightness | 22 (0.6) | 1 (0.1) | .0179 | OnabotA |
| Brow ptosis | 20 (0.6) | 0 | .0098 | OnabotA |
| Diarrhea | 7 (0.2) | 9 (0.7) | .0054 | Placebo |
| Eyelid edema | 12 (0.3) | 0 | .0214 | OnabotA |
| Facial pain | 12 (0.3) | 0 | .0285 | OnabotA |
| Lower RTI | 4 (0.1) | 6 (0.4) | .0129 | Placebo |
| Pneumonia | 3 (0.1) | 5 (0.4) | .0345 | Placebo |
| Rash | 2 (0.1) | 4 (0.3) | .0276 | Placebo |
| Gastroesophageal reflux disease | 1 (0.0) | 3 (0.2) | .0357 | Placebo |
| Periodontitis | 0 | 3 (0.2) | .0054 | Placebo |
| Visual impairment | 0 | 2 (0.1) | .0229 | Placebo |
| Adjustment disorder∗ | 0 | 1 (0.1) | .0438 | Placebo |
| Back injury | 0 | 1 (0.1) | .0443 | Placebo |
| Diabetes mellitus | 0 | 1 (0.1) | .0443 | Placebo |
| Fibromyalgia | 0 | 1 (0.1) | .0443 | Placebo |
| Gastrointestinal infection | 0 | 1 (0.1) | .0438 | Placebo |
| Leiomyoma | 0 | 1 (0.1) | .0443 | Placebo |
| Osteoarthritis | 0 | 1 (0.1) | .0443 | Placebo |
| Petechiae | 0 | 1 (0.1) | .0443 | Placebo |
| Perioral dermatitis | 0 | 1 (0.1) | .0443 | Placebo |
| Varicose vein | 0 | 1 (0.1) | .0443 | Placebo |
| Skin indentation | 0 | 1 (0.1) | .0443 | Placebo |
Included only statistically significant adverse events (P ≤ .050) across all treatment areas in the DBPC population. Statistical testing was based on a fixed-effects meta-analysis model using both the Peto method and the Mantel–Haenszel method. The minimum P value between the 2 methods is displayed.
DBPC, Double-blind placebo-controlled; OnabotA, onabotulinumtoxinA; RTI, respiratory tract infection.
With depressed mood.
An analysis was also performed for each treatment area for any AE and by individual preferred term. This showed a significantly higher overall incidence of AEs reported with onabotulinumtoxinA than placebo for the GL treatment area (Table VI), with similar findings for FHL/GL and FHL/GL/CFL, whereas AEs overall did not significantly differ for CFL and CFL/GL.
Table VI.
Adverse events across all treatment areas, filtered by P ≤ .050 across all groups (DBPC population, treatment cycle 1, days 1-90)
| Preferred term, n (%) | GL |
CFL |
CFL/GL |
FHL/GL |
FHL/GL/CFL |
All |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OnabotA N = 665 |
Placebo N = 236 |
OnabotA N = 1324 |
Placebo N = 808 |
OnabotA N = 405 |
Placebo N = 306 |
OnabotA N = 724 |
Placebo N = 315 |
OnabotA N = 313 |
Placebo N = 156 |
OnabotA N = 3431 |
Placebo N = 1359 |
|
| Overall | 282 (42.4) | 85 (36.0) | NS | NS | NS | NS | 273 (37.7) | 84 (26.7) | 122 (39.0) | 45 (28.8) | 1136 (33.1) | 395 (29.1) |
| Eyelid ptosis | 16 (2.4) | 0 | NS | NS | NS | NS | 15 (2.1) | 1 (0.3) | NS | NS | 34 (1.0) | 1 (0.1) |
| Eyelid sensory disorder | 21 (3.2) | 1 (0.4) | NS | NS | NS | NS | NS | NS | NS | NS | 25 (0.7) | 1 (0.1) |
| Skin tightness | NS | NS | NS | NS | NS | NS | 10 (1.4) | 0 | NS | NS | 22 (0.6) | 1 (0.1) |
| Brow ptosis | NS | NS | NS | NS | NS | NS | 11 (1.5) | 0 | NS | NS | 20 (0.6) | 0 |
| Eyelid edema | NS | NS | 5 (0.4) | 0 | NS | NS | NS | NS | NS | NS | 12 (0.3) | 0 |
| Diarrhea | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 7 (0.2) | 9 (0.7) |
| Facial pain | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 12 (0.3) | 0 |
| Lower RTI | NS | NS | 1 (0.1) | 3 (0.4) | NS | NS | NS | NS | NS | NS | 4 (0.1) | 6 (0.4) |
| Pneumonia | NS | NS | NS | NS | NS | NS | 0 | 2 (0.6) | NS | NS | 3 (0.1) | 5 (0.4) |
| Periodontitis | NS | NS | 0 | 2 (0.2) | NS | NS | NS | NS | NS | NS | 0 | 3 (0.2) |
| Adjustment disorder∗ | NS | NS | 0 | 1 (0.1) | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Back injury | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Diabetes mellitus | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Fibromyalgia | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Gastrointestinal infection | NS | NS | 0 | 1 (0.1) | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Leiomyoma | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Osteoarthritis | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Petechiae | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Skin indentation | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Varicose vein | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Injection site pruritus | 2 (0.3) | 4 (1.7) | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS |
| Rash | 0 | 3 (1.3) | NS | NS | NS | NS | NS | NS | NS | NS | 2 (0.1) | 4 (0.3) |
| Gastroesophageal reflux disease | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 1 (0.0) | 3 (0.2) |
| Visual impairment | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 2 (0.1) |
| Perioral dermatitis | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 0 | 1 (0.1) |
| Neck pain | 0 | 2 (0.8) | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS |
| Injection site hemorrhage | NS | NS | 8 (0.6) | 1 (0.1) | NS | NS | NS | NS | NS | NS | NS | NS |
| Cough | NS | NS | 6 (0.5) | 0 | NS | NS | NS | NS | NS | NS | NS | NS |
| Arthropod bite | NS | NS | 4 (0.3) | 0 | NS | NS | NS | NS | NS | NS | NS | NS |
| Injection site paresthesia | NS | NS | 4 (0.3) | 0 | NS | NS | NS | NS | NS | NS | NS | NS |
| Upper RTI | NS | NS | NS | NS | NS | NS | N/A | N/A | NS | NS | NS | NS |
| Dermatitis | NS | NS | 0 | 3 (0.4) | NS | NS | NS | NS | NS | NS | NS | NS |
| Vision blurred | NS | NS | 0 | 3 (0.4) | NS | NS | NS | NS | NS | NS | NS | NS |
| Dermatitis contact | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS |
| Eye pain | NS | NS | 0 | 2 (0.2) | NS | NS | NS | NS | NS | NS | NS | NS |
| Large intestine polyp | NS | NS | 0 | 1 (0.1) | NS | NS | NS | NS | NS | NS | NS | NS |
| Toothache | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS |
| Oral herpes | NS | NS | NS | NS | NS | NS | NS | NS | 2 (0.6) | 5 (3.2) | NS | NS |
| Head discomfort | NS | NS | NS | NS | NS | NS | 10 (1.4) | 0 | NS | NS | NS | NS |
| Nasopharyngitis | N/A | N/A | NS | NS | NS | NS | NS | NS | 22 (7.0) | 3 (1.9) | NS | NS |
Included only statistically significant adverse events (P ≤ .050) across all treatment areas in the DBPC population. For overall DBPC population, GL, CFL, and FHL/GL treatment areas, statistical testing was based on a fixed-effects meta-analysis model using both the Peto method and the Mantel–Haenszel method. The minimum P value between the 2 methods was used. For GL/CFL and FHL/GL/CFL treatment areas, statistical testing was based on Fisher’s exact tests.
CFL, Crow’s feet lines; DBPC, double-blind placebo-controlled; FHL, forehead lines; GL, glabellar lines; N/A, not applicable; NS, not significant; OnabotA, onabotulinumtoxinA, RTI, respiratory tract infection.
With depressed mood.
From the individual preferred term analysis, AEs favoring onabotulinumtoxinA were eyelid ptosis and eyelid sensory disorder for GL treatment; eyelid edema, injection site hemorrhage, cough, arthropod bite, and injection site paresthesia for CFL; eyelid ptosis, skin tightness, brow ptosis, and head discomfort for FHL/GL; and nasopharyngitis for FHL/GL/CFL (Table VII).
Table VII.
Adverse events across all treatment areas, filtered by P ≤ .050 and occurring more frequently in onabotulinumtoxinA than in placebo across all groups (DBPC population, treatment cycle 1, days 1-90)
| Preferred term, n (%) | GL |
CFL |
CFL/GL |
FHL/GL |
FHL/GL/CFL |
All |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OnabotA N = 665 |
Placebo N = 236 |
OnabotA N = 1324 |
Placebo N = 808 |
OnabotA N = 405 |
Placebo N = 306 |
OnabotA N = 724 |
Placebo N = 315 |
OnabotA N = 313 |
Placebo N = 156 |
OnabotA N = 3431 |
Placebo N = 1359 |
|
| Overall | 282 (42.4) | 85 (36.0) | NS | NS | NS | NS | 273 (37.7) | 84 (26.7) | 122 (39.0) | 45 (28.8) | 1136 (33.1) | 395 (29.1) |
| Eyelid ptosis | 16 (2.4) | 0 | NS | NS | NS | NS | 15 (2.1) | 1 (0.3) | NS | NS | 34 (1.0) | 1 (0.1) |
| Eyelid sensory disorder | 21 (3.2) | 1 (0.4) | NS | NS | NS | NS | NS | NS | NS | NS | 25 (0.7) | 1 (0.1) |
| Skin tightness | NS | NS | NS | NS | NS | NS | 10 (1.4) | 0 | NS | NS | 22 (0.6) | 1 (0.1) |
| Brow ptosis | NS | NS | NS | NS | NS | NS | 11 (1.5) | 0 | NS | NS | 20 (0.6) | 0 |
| Eyelid edema | NS | NS | 5 (0.4) | 0 | NS | NS | NS | NS | NS | NS | 12 (0.3) | 0 |
| Facial pain | NS | NS | NS | NS | NS | NS | NS | NS | NS | NS | 12 (0.3) | 0 |
| Injection site hemorrhage | NS | NS | 8 (0.6) | 1 (0.1) | NS | NS | NS | NS | NS | NS | NS | NS |
| Cough | NS | NS | 6 (0.5) | 0 | NS | NS | NS | NS | NS | NS | NS | NS |
| Arthropod bite | NS | NS | 4 (0.3) | 0 | NS | NS | NS | NS | NS | NS | NS | NS |
| Injection site paresthesia | NS | NS | 4 (0.3) | 0 | NS | NS | NS | NS | NS | NS | NS | NS |
| Head discomfort | NS | NS | NS | NS | NS | NS | 10 (1.4) | 0 | NS | NS | NS | NS |
| Nasopharyngitis | N/A | N/A | NS | NS | NS | NS | NS | NS | 22 (7.0) | 3 (1.9) | NS | NS |
Included only statistically significant adverse events (P ≤ .050) and occurring more frequently in the onabotulinumtoxinA treatment group across all treatment areas in the DBPC population. Statistical testing was based on a fixed-effects meta-analysis model using both the Peto method and the Mantel–Haenszel method. The minimum P value between the 2 methods was used.
CFL, Crow’s feet lines; DBPC, double-blind placebo-controlled; FHL, forehead lines; GL, glabellar lines; N/A, not applicable; NS, not significant; OnabotA, onabotulinumtoxinA.
Maximum cycle analysis
The effect of repeated onabotulinumtoxinA treatment was assessed in the population (N = 142) who received onabotulinumtoxinA for CFL (n = 82) or GL (n = 60) across 5 possible treatment cycles. The AEs most commonly associated with onabotulinumtoxinA injection (injection site pruritus, eyelid sensory disorder, eyelid ptosis) decreased between the first and fifth cycles (Table VIII). Overall, there was a trend toward reduced AEs with repeated onabotulinumtoxinA treatment.
Table VIII.
Adverse events by cycle occurring in ≥2 participants in the OnabotA group: maximum cycle analysis per treatment area
| Preferred term, n (%) | OnabotA: GL (n = 60) |
OnabotA: CFL (n = 82) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cycle 1 | Cycle 2 | Cycle 3 | Cycle 4 | Cycle 5 | Cycle 1 | Cycle 2 | Cycle 3 | Cycle 4 | Cycle 5 | |
| Overall | 28 (46.7) | 21 (35.0) | 27 (45.0) | 27 (45.0) | 14 (23.3) | 16 (19.5) | 16 (19.5) | 27 (32.9) | 18 (22.0) | 8 (9.8) |
| Nasopharyngitis | 5 (8.3) | 11 (18.3) | 11 (18.3) | 10 (16.7) | 1 (1.7) | 4 (4.9) | 5 (6.1) | 11 (13.4) | 3 (3.7) | 1 (1.2) |
| Injection site pruritus | 5 (8.3) | 1 (1.7) | 0 | 0 | 0 | 1 (1.2) | 0 | 0 | 0 | 0 |
| Eyelid ptosis | 3 (5.0) | 0 | 1 (1.7) | 0 | 0 | 0 | 0 | 0 | 1 (1.2) | 1 (1.2) |
| Eyelid sensory disorder | 2 (3.3) | 1 (1.7) | 0 | 1 (1.7) | 0 | 1 (1.2) | 1 (1.2) | 0 | 0 | 0 |
| Headache | 2 (3.3) | 2 (3.3) | 0 | 0 | 1 (1.7) | 1 (1.2) | 1 (1.2) | 0 | 0 | 0 |
| Back pain | 2 (3.3) | 0 | 1 (1.7) | 1 (1.7) | 1 (1.7) | 0 | 0 | 1 (1.2) | 2 (2.4) | 0 |
| Blood creatine phosphokinase | 0 | 0 | 3 (5.0) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Influenza | 0 | 0 | 1 (1.7) | 2 (3.3) | 0 | 0 | 0 | 0 | 1 (1.2) | 0 |
| Seasonal allergy | 0 | 0 | 1 (1.7) | 3 (5.0) | 0 | 0 | 0 | 0 | 0 | 0 |
| Injection site hemorrhage | 0 | 0 | 0 | 0 | 0 | 2 (2.4) | 1 (1.2) | 1 (1.2) | 1 (1.2) | 1 (1.2) |
| Upper respiratory tract inflammation | 2 (3.3) | 1 (1.7) | 0 | 0 | 0 | 0 | 1 (1.2) | 0 | 1 (1.2) | 0 |
| Abdominal pain upper | 1 (1.7) | 0 | 2 (3.3) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Purpura | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 (2.4) | 3 (3.7) | 1 (1.2) |
| Xeroderma | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 (2.4) | 0 | 0 |
| Blood cholesterol increased | 0 | 0 | 0 | 0 | 2 (3.3) | 0 | 0 | 0 | 0 | 0 |
| Eczema | 0 | 1 (1.7) | 0 | 2 (3.3) | 0 | 0 | 0 | 1 (1.2) | 0 | 0 |
| Rash | 1 (1.7) | 0 | 0 | 0 | 2 (3.3) | 0 | 0 | 0 | 0 | 0 |
OnabotA, OnabotulinumtoxinA.
Characterization of onabotulinumtoxinA model–generated significant AEs
AEs of interest in onabotulinumtoxinA-treated participants, including eyelid ptosis, eyelid sensory disorder, skin tightness, brow ptosis, eyelid edema, and facial pain, occurred in the first 90 days of treatment cycle 1 for the DBPC population and were of mild to moderate severity (Table VII). Most occurred within the first week and generally resolved within a few weeks of treatment.
Eyelid ptosis
There were 37 cases of eyelid ptosis in 34 participants (1.0%), described verbatim as, for example, “eyelid ptosis,” “drooping upper eyelid-bilateral,” and “bilateral heavy eyelid.” Thirty (81.1%) were mild in severity; the remainder were moderate. Most (81.1%) were reported within 14 days of treatment with a median onset of 9 days. Almost half (48.6%) of the cases resolved within 28 days of onset. The median duration was 28 days.
Eyelid sensory disorder
Twenty-five cases of eyelid sensory disorder were reported in 25 participants (0.7%); verbatim terms included “heavy feeling eyelids” and “feeling of impaired lid function.” All were mild except for 1 of moderate severity. Most (88.0%) were reported within 14 days of treatment. Median onset was 4 days; 60% resolved within 28 days of onset. The median duration was 15 days.
Skin tightness
Twenty-two cases of skin tightness were reported in 22 participants (0.6%); verbatim descriptions included “tight feeling at forehead,” “forehead skin tightness,” and “raised lateral superciliary arch.” Twenty (90.9%) were mild in severity; the rest were moderate. All but 1 case (95.5%) were reported within 14 days of treatment; median onset was 4.5 days. One case resolved within 24 hours, and 13 (59.1%) resolved within 28 days of onset. The median duration was 19 days.
Brow ptosis
Twenty cases of eyebrow ptosis were reported in 20 participants (0.6%); verbatim descriptions included “feeling of brow heaviness,” “eyebrow ptosis,” and “heavy brow.” Three (15.0%) were moderate in severity, 1 had a missing severity, and the remainder were mild. All but 1 case (95%) were reported within 14 days of treatment; median onset was 6 days. Forty percent of the cases resolved within 28 days, and 1 resolved within 24 hours. The median duration was 44 days.
Eyelid edema
Thirteen cases of eyelid edema were reported in 12 participants (0.3%); verbatim descriptions included “eyelid edema,” “palpebral edema right and left not at the site of injection,” and “lymphoedema lower eye lids both sides, not injection.” All were mild in severity. Eleven cases (84.6%) were reported within 14 days of treatment; median onset was 5.0 days. Nine cases (69.2%) resolved within 28 days of onset. The median duration was 14 days.
Facial pain
Twelve cases of facial pain, all mild, were reported in 12 participants (0.3%); verbatim descriptions included “discomfort between brows,” “tenderness in glabella area,” and “pain at forehead.” Ten cases (83.3%; median onset, 1 day) were reported within 2 weeks of treatment. Two cases occurred at days 29 and 52 after treatment. All cases resolved within 8 days, with a median duration of 2 days.
Serious AEs (SAEs)
SAEs were reported in 54 (1.6%) and 17 (1.3%) of the onabotulinumtoxinA and placebo groups, respectively (Table IX). Only 1 (spontaneous abortion) was considered possibly treatment related. The subject had a negative pregnancy test before receiving a single treatment of onabotulinumtoxinA for CFL. Nineteen days after treatment, the patient reported a possible pregnancy, confirmed to be twins by a gynecologist 2 days later. Within 1 week later, the patient spontaneously expelled 1 fetus and the second was subsequently medically removed due to lack of viability.
Table IX.
Serious adverse events occurring in ≥2 participants across all treatment areas (DBPC population, by treatment area)
| Preferred term, n (%) | GL |
CFL |
CFL/GL |
FHL/GL |
FHL/GL/CFL |
All |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OnabotA N = 665 |
Placebo N = 236 |
OnabotA N = 1324 |
Placebo N = 808 |
OnabotA N = 405 |
Placebo N = 306 |
OnabotA N = 724 |
Placebo N = 315 |
OnabotA N = 313 |
Placebo N = 156 |
OnabotA N = 3431 |
Placebo N = 1359 |
|
| Overall | 10 (1.5) | 2 (0.8) | 18 (1.4) | 12 (1.5) | 11 (2.7) | 7 (2.3) | 10 (1.4) | 3 (1.0) | 5 (1.6) | 2 (1.3) | 54 (1.6) | 17 (1.3) |
| Basal cell carcinoma | 0 (0.0) | 0 (0.0) | 4 (0.3) | 0 (0.0) | 2 (0.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 6 (0.2) | 0 (0.0) |
| Breast cancer | 2 (0.3) | 0 (0.0) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.1) | 1 (0.1) |
| Myocardial infarction | 0 (0.0) | 0 (0.0) | 2 (0.2) | 1 (0.1) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.1) | 1 (0.1) |
| Pneumonia | 0 (0.0) | 0 (0.0) | 1 (0.1) | 1 (0.1) | 1 (0.2) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.1) | 1 (0.1) |
| Intervertebral disc protrusion | 1 (0.2) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.1) | 0 (0.0) |
| Invasive ductal breast carcinoma | 0 (0.0) | 0 (0.0) | 2 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.1) | 0 (0.0) |
| Overdose∗ | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.1) | 0 (0.0) |
Included only serious adverse events occurring in ≥2 participants in either treatment group across all treatment areas in the DBPC population.
CFL, Crow’s feet lines; DBPC, double-blind placebo-controlled; FHL, forehead lines; GL, glabellar lines; onabotA, onabotulinumtoxinA.
Overdose of alcohol, gabapentin, and zopiclone (n = 1) and of alcohol and co-codamol 30/500 (n = 1).
PDSOT
A detailed medical review of AE reports containing ≥1 MedDRA term used to analyze PDSOT (Table I) revealed no relation to distant spread of toxin. All AEs reviewed were confirmed to be consistent with known local spread events associated with the treatment area.
Discussion
This updated meta-analysis expands on the safety data previously reported for onabotulinumtoxinA for GL and CFL,7 more than tripling the number of participants and reporting on additional facial aesthetic indications. The onabotulinumtoxinA safety profile for facial aesthetic indications remained consistent with the product label, and no new signals emerged from pooling populations. At approved onabotulinumtoxinA doses, local AEs and incidences were relevant to the treatment area, and maximum cycle analysis did not indicate increased risk from greater cumulative dose across multiple areas. Moreover, both repeat and long-term treatment (ie, >12 months) did not affect the AE risk over time (Table VIII).
This meta-analysis expands current knowledge of the safety and tolerability of onabotulinumtoxinA in the context of aesthetic treatment of upper facial lines, which generally uses lower and less-frequent dosing compared with therapeutic indications such as adult upper limb spasticity.28,29 Accepted statistical methods were used to confirm the relevance of existing AEs. Descriptive statistics showed that among the most common AEs favoring onabotulinumtoxinA, 2 were likely procedure related (injection site bruising and injection site hematoma). When fixed-effects statistical modeling was applied to the pooled AEs of the DBPC population across all treatment areas, 24 individual AEs were identified statistically. These AEs statistically favored either onabotulinumtoxinA (n = 6) or placebo (n = 18) (Table V). However, most occurred in very low numbers, especially in the placebo group, where 12 of the 18 AEs were reported in 1 or 2 subjects across all treatment areas. Upon medical review, the 12 AEs were not considered clinically meaningful but rather a consequence of the fixed-effects model used to evaluate significance between onabotulinumtoxinA and placebo in the pooled incidence of each AE. The disproportionately small ratio of patients receiving placebo versus onabotulinumtoxinA may have also influenced this statistical outcome.
When the analysis was performed by individual preferred term for each treatment area, significant AEs favoring onabotulinumtoxinA for at least 1 treatment area were eyelid ptosis, eyelid sensory disorder, eyelid edema, skin tightness, brow ptosis, facial pain, injection site hemorrhage, cough, arthropod bite, injection site paresthesia, head discomfort, and nasopharyngitis. After medical review excluded AEs unrelated to treatment, the remaining model-generated significant AEs (all P < .03) were eyelid ptosis, eyelid sensory disorder, skin tightness, brow ptosis, eyelid edema, and facial pain (Table VII). Of these AEs, only eyelid ptosis was identified as having a frequency of at least 1% in the descriptive statistical analysis (Table IV). Furthermore, all had been previously associated with onabotulinumtoxinA upper facial line treatments and none were deemed related to PDSOT.
The prior analysis of GL studies had revealed 3 AEs with a significantly higher incidence in onabotulinumtoxinA-treated subjects: eyelid ptosis, eyelid sensory disorder, and eyelid edema.7 With the inclusion of additional safety results from CFL and FHL studies in the present analysis, eyebrow ptosis, facial pain, and skin tightness were also revealed as significant AEs associated with onabotulinumtoxinA treatment. When analyzed by treatment area, eyelid ptosis and eyelid sensory disorder were significant AEs favoring onabotulinumtoxinA with GL treatment; eyelid ptosis, skin tightness, and brow ptosis were associated with FHL/GL; eyelid edema was significant for CFL; and facial pain showed no significance in any single treatment area but was significantly higher than placebo in the pooled DBPC population. These AEs are expected local effects to the muscle groups injected for each treatment area.
One AE of spontaneous abortion was considered possibly treatment related by the investigator. It involved a twin pregnancy and occurred early in the first trimester in a subject with no known past pregnancy. Spontaneous abortion and fetal defects have been reported with onabotulinumtoxinA treatment.30,31 A recent 29-year retrospective study of the Allergan safety database reviewed the pregnancy outcomes of 397 mothers worldwide, a majority of whom (n = 202 of the 242 pregnancies where dosage was reported) were exposed to <200 U of onabotulinumtoxinA during or within 3 months prior to pregnancy.31 Of the 195 pregnancies that were recorded prospectively, 77.2% resulted in live births. The incidence of fetal loss due to spontaneous abortion was 16.2%. The prevalence of these outcomes was consistent with rates reported in the general population, where spontaneous abortion is expected to occur in approximately 20% of known pregnancies in the U.S.32
Strengths of this study are that the analysis is based on prospective, longitudinal data drawn from 5298 participants, 4449 of whom were treated with onabotulinumtoxinA in upper facial areas in DBPC clinical studies. These were conducted for product registrations; thus, they were robust in scope and quality. In addition, the clinical studies analyzed were conducted using accepted meta-analytic methods and had a high degree of homogeneity as assessed by the Q statistic and I2 index.
Study limitations include clinical trial design whereby the safety data analyzed are primarily based on studies lasting a year or less and excluding patients with severe medical disease. In addition, whereas the fixed-effects modeling method provides an additional means for detecting significant AEs, medical review is necessary to contextualize these events in practice.
Conclusions
This meta-analysis of safety data from 5298 participants confirmed the safety and tolerability of onabotulinumtoxinA for dynamic upper facial lines treatment (GL, CFL, and FHL), using accepted statistical methodologies. The AEs were generally mild to moderate in severity, and treatment-related AEs represented local pharmacologic or injection-associated responses. No new safety signals emerged from the pooled populations.
Conflicts of interest
MF Brin, I Yushmanova, TI Boodhoo, and E Lee are employees of Allergan Aesthetics, an AbbVie Company, and may hold AbbVie stock. K De Boulle serves as a consultant and member of speaker boards for Allergan Aesthetics, an AbbVie Company, Laboratoires Genevrier, and IBSA. S Liew reports no conflicts. A Carruthers and J Carruthers serve as consultants and investigators for Allergan Aesthetics, an AbbVie Company, Alphaeon, Merz Aesthetics, Revance, and Zeltig. A Rivkin serves as a consultant and investigator for Allergan Aesthetics, an AbbVie Company, and Merz Aesthetics. Y Wu has served as an investigator for Allergan Aesthetics, an AbbVie Company. M Kawashima has no conflicts to disclose. The authors did not receive honoraria or any other form of compensation for authorship or other activities related to the preparation or submission of this manuscript.
Acknowledgments
Medical writing was provided by Regina Kelly, MA and Barbara Zeman, PhD of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and was funded by Allergan Aesthetics, an AbbVie Company, Irvine, CA. The authors thank Kathy Zhuang, MS for her contributions to the development of this manuscript, during which time, she was an employee of Allergan Aesthetics, an AbbVie Company.
Footnotes
Funding sources: Allergan Aesthetics, an AbbVie Company, funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. Medical writing support was provided by Regina Kelly, MA and Barbara Zeman, PhD of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by Allergan Aesthetics, an AbbVie Company.
Patient consent: Not applicable.
IRB approval status: All studies complied with the Declaration of Helsinki, included written informed consent, and were approved by an institutional review board.
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