Safety and tolerability of onabotulinumtoxinA in the treatment of facial lines: A meta-analysis of individual patient data from global clinical registration studies in 1678 participants

Accepted 8 June 2009. published online 10 September 2009.

Background

OnabotulinumtoxinA for the treatment of facial lines is a widely used cosmetic medical procedure and, as such, the safety and tolerability profile is of interest to health care providers and patients. Based on data from individual studies that were conducted according to regulatory guidelines to provide adequate safety and efficacy data to support product licensure (registration studies), the overall benefit:risk profile of onabotulinumtoxinA for facial lines has been favorable.

Objective

Our objective was to increase statistical power through meta-analysis to detect treatment group differences in adverse event (AE) incidence that may not have been evident in individual registration studies.

Methods

Individual participant data (n = 1678) were from 6 randomized, double-blind, placebo-controlled and 3 open-label studies. Two double-blind, placebo-controlled studies were for lateral canthal lines (3-18 U/side) and all others were for glabellar lines (10 or 20 U). Doses used reflect global product labeling in countries where licensed.

Results

Participant population was non-Hispanic white (43%) or Asian (52%) and predominantly female (88%). In double-blind, placebo-controlled studies, overall AE incidence did not significantly differ by treatment group (onabotulinumtoxinA vs placebo). The only individual AEs with significantly greater incidence in the onabotulinumtoxinA group were eyelid sensory disorder (2.5% vs 0.3%, P = .004; verbatim phrases “tight,” “pressured,” “heavy,” “drooping feeling,” “feeling of droopiness”) and eyelid ptosis (1.8% vs 0%, P = .02), both present only in glabellar studies. Overall treatment-related (per investigator) AE incidence was greater in the onabotulinumtoxinA group versus placebo (24% vs 16%, P = .005), and treatment-related eyelid edema was an additional AE with significantly higher incidence in the onabotulinumtoxinA group versus placebo (P = .04). Incidence of all 3 of these AEs significantly decreased as number of treatment cycles increased. Eyelid sensory disorder and eyelid edema were more common in Asian participants. Acne, injection site pruritus, oral herpes, rash, lower respiratory tract infection, dental caries, and eye pain were significantly more common in placebo-treated compared with onabotulinumtoxinA-treated participants. Serious AE incidence did not significantly differ by treatment (onabotulinumtoxinA vs placebo) and no serious AEs were treatment related. There were no symptoms of weakness remote to the injection site or related to the central nervous system.

Limitations

Limitations included: (1) highly visible efficacy of onabotulinumtoxinA may have resulted in reporting bias; (2) reliance on participant intervisit recall; (3) a relatively short follow-up period (1 year); (4) conclusions are based solely on the doses analyzed (ie, those used in the respective trials); and (5) exclusion of patients with severe medical disease in registration studies.

Conclusion

This meta-analysis confirms the safety and tolerability of onabotulinumtoxinA for glabellar and lateral canthal lines, at the doses studied, based on the most comprehensive controlled safety analysis of onabotulinumtoxinA performed to date. The AEs observed were generally mild to moderate; most treatment-related AEs were related either to physical injection of product or local pharmacologic effects. Even with the increased statistical power of a large sample size, no new onabotulinumtoxinA-associated AEs emerged.

Key words: aesthetic, botulinum toxin, cosmetic, crow's-feet, glabellar lines, onabotulinumtoxinA, rhytids, safety, tolerability

Abbreviations used: AE, adverse event, CF, crow's-feet, DBPC, double-blind, placebo-controlled, GL, glabellar lines, MedDRA, Medical Dictionary for Regulatory Activities, OL, open-label, SAE, serious adverse event, TRAE, treatment-related adverse event

a Allergan, Irvine, California

b University of California, Irvine, California

c University of Southern California, Los Angeles, California

d independent contractor, Corvallis, Montana

e GlaxoSmithKline K.K., Shibuya-ku, Tokyo

f GlaxoSmithKline China Investment Co Ltd, Shanghai, China

Reprint requests: Mitchell F. Brin, MD, Allergan, 2525 Dupont Dr, T1-1B, Irvine, CA 92623-9534.

The writing of the manuscript and associated statistical analyses were funded by Allergan. All studies reported herein were funded by the sponsoring pharmaceutical companies: Allergan, GlaxoSmithKline Japan, and GlaxoSmithKline China.

Disclosure: Dr Brin, Mr Boodhoo, Ms James, Dr Demos, Dr Terashima, Ms Gu, and Ms Bowen are employed by the pharmaceutical companies and receive direct salary compensation. Dr Brin, Ms Eadie, Ms Bowen, Mr Boodhoo, Dr Demos, and Ms James also hold an equity interest in the companies in the form of stock, stock options, or both. Dr Pogoda and Ms Eadie have consulting contracts with Allergan. None of the authors have any commercial associations with any company that makes a competing product. No ghost writers or other third parties were involved in the preparation of the manuscript.

PII: S0190-9622(09)00725-7

doi:10.1016/j.jaad.2009.06.040

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