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Botox

Clinical Pharmacology
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CLINICAL PHARMACOLOGY

Botox

BOTOX® blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings.

When injected intramuscularly at therapeutic doses, BOTOX® 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®.

When injected intradermally, BOTOX® produces temporary chemical denervation of the sweat gland resulting in local reduction in sweating.

Pharmacokinetics

Botulinum Toxin Type A is not expected to be present in the peripheral blood at measurable levels following IM or intradermal injection at the recommended doses. The recommended quantities of neurotoxin administered at each treatment session are not expected to result in systemic, overt distant clinical effects, i.e. muscle weakness, in patients without other neuromuscular dysfunction. However, sub-clinical systemic effects have been shown by single-fiber electromyography after IM doses of botulinum toxins appropriate to produce clinically observable local muscle weakness.

CLINICAL STUDIES

Cervical Dystonia:

A phase 3 randomized, multi-center, double blind, placebo-controlled study of the treatment of cervical dystonia was conducted.1 This study enrolled adult patients with cervical dystonia and a history of having received BOTOX® in an open label manner with perceived good response and tolerable side effects. Patients were excluded if they had previously received surgical or other denervation treatment for their symptoms or had a known history of neuromuscular disorder. Subjects participated in an open label enrichment period where they received their previously employed dose of BOTOX®. Only patients who were again perceived as showing a response were advanced to the randomized evaluation period. The muscles in which the blinded study agent injections were to be administered were determined on an individual patient basis.

There were 214 subjects evaluated for the open label period, of which 170 progressed into the randomized, blinded treatment period (88 in the BOTOX® group, 82 in the placebo group). Patient evaluations continued for at least 10 weeks post-injection. The primary outcome for the study was a dual endpoint, requiring evidence of both a change in the Cervical Dystonia Severity Scale (CDSS) and an increase in the percentage of patients showing any improvement on the Physicians Global Assessment Scale at 6 weeks after the injection session. The CDSS quantifies the severity of abnormal head positioning and was newly devised for this study. CDSS allots 1 point for each 5 degrees (or part thereof) of head deviation in each of the three planes of head movement (range of scores up to theoretical maximum of 54). The Physician Global Assessment Scale is a 9 category scale scoring the physician’s evaluation of the patients’ status compared to baseline, ranging from -4 to +4 (very marked worsening to complete improvement), with 0 indicating no change from baseline and +1 slight improvement. Pain is also an important symptom of cervical dystonia and was evaluated by separate assessments of pain frequency and severity on scales of 0 (no pain) to 4 (constant in frequency or extremely severe in intensity). Study results on the primary endpoints and the pain-related secondary endpoints are shown in Table 1.

Table 1: Efficacy Outcomes of The Phase 3 Cervical Dystonia Study (Group Means)

Brand Name: Botox
Generic Name: Botulinum Toxin Type A
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