Botulinum Toxin A (Botox® Cosmetic)

Abstract

Abstract

Botox® Cosmetic (Botox®) is a formulation of the neuromuscular blocking agent botulinum toxin type A (BTX-A). When injected into hyperactive corrugator superciliaris and/or procerus muscles of the face that predominantly control frowning, Botox® produces a transient (3- to 6-month), dose-dependent localized muscle weakness, resulting in a temporary improvement in glabellar frown lines (‘brow furrows’).

After a decade of successful ‘off-label’ use, the efficacy and tolerability of Botox® (total dose 20 biological units) in the treatment of glabellar frown lines have been demonstrated in two identical, large, multicenter, randomized, double-blind, placebo-controlled pivotal trials in a total of 537 subjects, mostly women, with moderate or severe glabellar lines during facial animation. Based both on subjects’ and physicians’ assessments, the improvement in glabellar lines with Botox® was superior to that with placebo at each visit during the 120-day post-injection follow-up period, beginning on day 7 post-injection. The peak effect was seen on day 30 post-injection when 80% of subjects in the two studies combined had the severity of their lines at maximum frown reduced to mild or none, as assessed by their physician, and 89% had at least a moderate (≥50%) improvement in the appearance of their glabellar lines, as rated by themselves. In a noncomparative extension of these trials, there was a tendancy for a higher proportion of subjects to respond to Botox® injections after a second and third treatment session.

Botox® injections for glabellar lines are well tolerated. Headache, the most common adverse event, occurred with a similar frequency to placebo in the two pivotal studies (13% vs 18%). Temporary blepharoptosis occurred in 3.2% of Botox® recipients; however, the incidence of this adverse event tended to decrease with repeated treatment sessions.

In summary, Botox® injections offer a convenient, effective, and well tolerated treatment for improving glabellar frown lines. Repeated injections are necessary to maintain a long-term effect; however, this technique clearly represents an attractive option for individuals who wish to avoid a more major procedure.

Pharmacological Properties

Botox® Cosmetic (Botox®) is a formulation of botulinum toxin A (BTX-A) purified neurotoxin complex, which is produced by fermentation of Clostridium botulinum type A (Hall strain).

When injected into striated muscles, BTX-A produces a dose-dependent local muscle weakness by preventing the release of acetylcholine from nerve terminals at the neuromuscular junction. This inhibition occurs as a result of a four-step process that culminates with the cleavage of the 25kD synaptosome-associated protein, which is essential for the exocytosis of acetylcholine. However, the paralytic effect is only temporary due to the gradual recovery of functional activity in the originally chemo-denervated terminals over a period of 3 months or longer.

In early, mostly noncomparative, clinical studies, the localized muscle weakness produced by injecting Botox® into hyperactive corrugator superciliaris and/or procerus muscles of the face that predominantly control frowning started 1–3 days after the injection and lasted 3–6 months. The result was a temporary improvement in glabellar frown lines (‘brow furrows’).

The total dose of Botox® recommended for the treatment of glabellar frown lines is two orders of magnitude below the 2500–3000U dose estimated to be lethal to half the 70kg adult population. Moreover, it is highly unlikely to lead to the formation of neutralizing antibodies.

Botox® is not expected to be present in the peripheral blood at measurable quantities following proper placement of the toxin at the recommended doses by intramuscular injection, although this has not been formally studied. The results of a single-fiber electromyographic study in patients receiving periocular injections of BTX-A for blepharospasm indicate the potential for the toxin to spread remotely from the site of injection. Although not detectable clinically, abnormal neuromuscular transmission in arm muscles was measurable electromyographically.

Cosmetic Efficacy

A decade of ‘off-label’ clinical experience in mostly small, noncomparative studies showing that Botox® is highly effective in the temporary treatment of glabellar frown lines has been confirmed in two identical, large, multicenter, randomized, double-blind, placebo-controlled, phase III trials, which enrolled a total of 537 subjects (>80% of whom were women) with moderate to severe lines at maximum frown.

According to both the physician’s assessment of glabellar line severity at maximum frown and the subject’s global assessment of the change in appearance of their glabellar lines, Botox® injection (total dose 20U, n = 405) improved glabellar lines to a significantly greater extent than placebo (n = 132) at every visit during the 120-day post-injection follow-up period (p < 0.001). Based on these efficacy endpoints (mean score or responder rate analysis), the effect of treatment was apparent within 7 days; the magnitude of the improvement at this time was only slightly less than the peak effect, which was seen on post-injection day 30. Thereafter, the effect of treatment gradually declined (consistent with the slow reversal of Botox®-induced local muscle weakness), but was still apparent on post-injection day 120. Pooled responder rates based on the physician’s assessment at maximum frown and the subject’s global assessment were, respectively, 80% and 89% on post-injection day 30 and 25% and 39% on post-injection day 120. Similar results were obtained for the physician’s assessment of glabellar line severity at rest efficacy endpoint and, interestingly, the reduction in severity at rest was sustained at a high level for longer than that at maximum frown.

Subgroup analyses based on the physician’s assessment of glabellar line severity at maximum frown and the subject’s global assessment of the change in appearance of their glabellar lines suggest that individuals aged ≤50 years respond better to Botox® treatment than those aged ≥51 years, and that women respond better than men, although no between-group statistical comparisons have been performed. Response rates with Botox® were numerically greater than those with placebo, irrespective of age and gender.

In a noncomparative extension of the double-blind trials, responder rates for each of the three efficacy endpoints tended to increase across the treatment sessions in 258 subjects who received three Botox® treatments (20U every 120 days) over a 1-year period. Responder rates on day 30 post-injection after the first, second and third Botox® treatments were 80%, 86% and 89%, respectively, for the physician’s assessment at maximum frown, 89%, 92% and 90% for the subject’s global assessment, and 75%, 90% and 91% for the physician’s assessment at rest.

Tolerability

Botox® (total dose 20U) was well tolerated based on a pooled analysis of the two large placebo-controlled trials (n = 537). Headache, the most common adverse event, occurred in 13% of Botox® recipients in these studies; however, it occurred with a similar frequency in placebo recipients (18%). Temporary blepharoptosis, the most notable adverse event, occurred in significantly more Botox®- than placebo-treated subjects (3.2% vs 0%, p = 0.045). However, the incidence of blepharoptosis tended to decrease after a second and third Botox® treatment session in the noncomparative extension study.

Weakness in the injected muscle(s) [reported in 2% of Botox® recipients vs 0% of placebo recipients] is an expected consequence of Botox® administration, while that in adjacent muscles is due to migration of the toxin. Episodes of muscle weakness occur within 7 days of the Botox® injections and are generally transient. Injection site-related adverse events (e.g. pain, erythema, ecchymosis, edema) were reported in ≈1–2% of subjects in the controlled trials. No details are available on the severity and duration of these reactions; however, results from earlier small, noncomparative studies suggest that they are often mild and transient.

Dosage and Administration

In the US, intramuscular injection of Botox® is indicated for the temporary improvement in the appearance of moderate to severe glabellar frown lines associated with corrugator and/or procerus muscle activity in adults aged ≤65 years.

The US prescribing information recommends injecting 0.1mL of the properly reconstituted toxin (40 U/mL) into five sites (two in each corrugator muscle and one in the procerus muscle) for a total dose of 20U; the interval between injections should be no less than 3 months, and the lowest effective dose of toxin should be used.

To minimize the risk of blepharoptosis, Botox® injections should not be placed near the levator palpebrae superioris or <1cm above the central eyebrow; medial corrugator injections should be placed ≥1cm above the bony supraorbital ridge.