July 26, 2016
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"The U.S. Food and Drug Administration today approved Botox injection (onabotulinumtoxinA) to prevent headaches in adult patients with chronic migraine. Chronic migraine is defined as having a history of migraine and experienci"...




Mechanism Of Action

BOTOX Cosmetic blocks neuromuscular transmission by binding to acceptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a pre-synaptic protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX Cosmetic produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX Cosmetic.


No formal pharmacodynamic studies have been conducted with BOTOX Cosmetic (onabotulinumtoxinA) for injection.


Using currently available analytical technology, it is not possible to detect BOTOX Cosmetic in the peripheral blood following intramuscular injection at the recommended doses.

Clinical Studies

Glabellar Lines

Two phase 3 randomized, multi-center, double-blind, placebo-controlled trials of identical design were conducted to evaluate BOTOX Cosmetic for use in the temporary improvement of the appearance of moderate to severe glabellar facial lines. The trials enrolled healthy adults (ages 18 to 75) with glabellar lines of at least moderate severity at maximum frown. Subjects were excluded if they had ptosis, deep dermal scarring, or an inability to substantially lessen glabellar lines even by physically spreading them apart. Subjects received a single treatment with BOTOX Cosmetic (N=405, combined trials) or placebo (N=132, combined trials). Injection volume was 0.1 mL/injection site, for a dose/injection site in the active treatment groups of 4 Units. Subjects were injected intramuscularly in five sites, 1 in the procerus muscle and 2 in each corrugator supercilii muscle, for a total dose in the active treatment groups of 20 Units.

The co-primary efficacy endpoints were the investigator's rating of glabellar line severity at maximum frown and the subject's global assessment of change in appearance of glabellar lines, both at Day 30 post-injection. For the investigator rating, using a 4-point grading scale (0=none, 3=severe) a responder was defined as having a severity grade of 0 or 1. For the subject's global assessment of change, the ratings were from +4 (complete improvement) to -4 (very marked worsening). A responder was defined as having a grade of at least +2 (moderate improvement). After completion of the randomized studies, subjects were offered participation in an open label, repeat treatment study to assess the safety of repeated treatment sessions.

The combined results of these two efficacy trials are presented here. The mean age was 46 years, with 32 subjects (6%) ≥ 65 years of age. Most of the subjects were women (82%), and Caucasian (84%). At baseline, 210 subjects (39%) had glabellar line severity scores at rest of moderate or severe.

In these trials, the severity of glabellar lines was reduced for up to 120 days in the BOTOX Cosmetic group compared to the placebo group as measured both by investigator rating of glabellar line severity at maximum frown (Table 4), and by subject's global assessment of change in appearance of glabellar lines (Table 5).

Table 4: Investigator's Assessment of Glabellar Line Severity at Maximum Frown – Responder Rates (% and Number of Subjects with Severity of None or Mild)

Day BOTOX Cosmetic Placebo Differencea
7 74% 6% 68%
299/405 8/132 (62, 74)
30b 80% 3% 77%
325/405 4/132 (72, 82)
60 70% 2% 69%
283/403 2/130 (64, 74)
90 48% 2% 45%
192/403 3/128 (40, 51)
120 25% 2% 24%
102/403 2/128 (19, 29)
a 95% confidence intervals are shown in parenthesis
b Day 30: Co-Primary Efficacy Time point, p < 0.001

Table 5: Subject's Assessment of Change in Appearance of Glabellar Lines – Responder Rates (% and Number of Subjects with at Least Moderate Improvement)

Day BOTOX Cosmetic Placebo Differencea
7 82% 9% 73%
334/405 12/132 (68, 80)
30b 89% 7% 83%
362/405 9/132 (77, 88)
60 82% 4% 78%
330/403 5/130 (73, 83)
90 63% 3% 60%
254/403 4/128 (54, 66)
120 39% 1% 38%
157/403 1/128 (33, 43)
a 95% confidence intervals are shown in parenthesis
b Day 30: Co-Primary Efficacy Time point, p < 0.001

In the subset of subjects with resting severity scores of moderate or severe, the investigator assessment of a resting severity of mild or none at Day 30 was also achieved by more BOTOX Cosmetic treated subjects (74%, 119/161) than placebo treated subjects (20%, 10/49).

Analysis of the limited number of subjects 65 years or older suggested a lower treatment-associated response compared to subjects less than 65 years of age (Table 6).

Table 6: Investigator's and Subject's Assessment – Responder Rates for Subjects < 65 and ≥ 65 Years of Age at Day 30

Assessment Age Group BOTOX Cosmetic
Investigators (maximal frown) < 65 83% 2% 81%
316/382 2/123 (77, 86)
Subjects < 65 91% 7% 84%
346/382 8/123 (79, 90)
Investigators (maximal frown) ≥ 65 39% 22% 17%
9/23 2/9 (-17, 51)
Subjects ≥ 65 70% 11% 58%
16/23 1/9 (31, 86)
a 95% confidence intervals are shown in parenthesis

Exploratory analyses by gender suggested that responder rates in the BOTOX Cosmetic treated group were higher for women than for men for both the investigator assessment (Day 30; 85% of 334 women, 59% of 71 men) and the Subject Assessment (Day 30; 93% of women, 72% of men). In the limited number of non-Caucasian subjects (n=64 in the BOTOX Cosmetic treated group) the responder rates were similar to those observed in the Caucasian subjects.

Lateral Canthal Lines

Two multicenter, randomized, double-blind, placebo-controlled trials evaluated BOTOX Cosmetic (N=833, randomized to receive any BOTOX Cosmetic treatment or N=529 randomized to receive placebo) for the temporary improvement in the appearance of moderate to severe lateral canthal lines (LCL). Study 1 assessed BOTOX Cosmetic treatment of LCL alone; Study 2 also assessed simultaneous treatment of LCL and glabellar lines (GL). Both trials enrolled healthy adults with moderate to severe LCL at maximum smile at baseline; Study 2 also required subjects to have moderate to severe GL at maximum frown at baseline.

In the 5-month Study 1, subjects were randomized to receive a single blinded treatment of 24 Units/0.6 mL (12 Units per side) consisting of 4 Units/0.1 mL into 3 sites of each orbicularis oculi muscle with either BOTOX Cosmetic (N=222) or placebo (N=223).

In the 7-month Study 2, subjects were randomized to receive either BOTOX Cosmetic in the LCL region and placebo in the GL region (24 Units; N=306), or BOTOX Cosmetic in the LCL and GL regions (44 Units [24 Units for LCL and 20 Units for GL]; N=305), or placebo in the LCL and GL regions (0 Units; N=306). Subjects received the same 24 Units regimen for LCL as in Study 1, and the labeled 20 Units (5 injections, 4 Units per site) for GL. Subjects received the same treatment at days 1 and 120.

The primary efficacy measure was the assessment of LCL severity at maximum smile using the 4-point Facial Wrinkle Scale with Photonumeric Guide (FWS; 0=none, 1= mild, 2=moderate, 3=severe). The FWS assessment was performed independently by both investigators and subjects. The primary timepoint was day 30 following the first treatment, as compared to baseline.

The primary efficacy response definition used for the pivotal trials was a composite ≥ 2-grade improvement from baseline in LCL severity at maximum smile, assessed by both investigator and subject on a per-subject basis. For Studies 1 and 2, the proportion of responders was statistically significant favoring BOTOX Cosmetic (24 Units [LCL alone] and 44 Units [LCL and GL]) compared to placebo at day 30 (Table 7).

Table 7: Studies 1 and 2: Composite Investigator and Subject Assessment of LCL at Maximum Smile at Day 30 – Responder Rates (% and Number of Subjects Achieving ≥ 2-Grade Improvement from Baseline)

Study BOTOX Cosmetic 24 Units BOTOX Cosmetic 24 Units LCL and 20 Units GL Placebo
Study 1 26.1% - 1.3%
58/222 3/223
Study 2 20.3% 21.3% 0.0%
62/306 65/305 0/306

The secondary endpoint of a responder defined as achieving a grade of none or mild for Study 1 as measured by the investigator is presented in Figure 4 below.

Figure 4: Percentage of Subjects with Treatment Success (% of Subjects achieving None or Mild from Baseline) by Visit (Study 1)

Percentage of Subjects with Treatment Success - Illustration

Last reviewed on RxList: 5/17/2016
This monograph has been modified to include the generic and brand name in many instances.

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