Botox (onabotulinumtoxinA)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved March 2010

Specific Treatments:

upper limb spasticity

General Information

Botox for injection is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A. 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. Acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system and causes the activation of muscle movement.

Among other indications, Botox has been approved specifically for upper limb spasticity in adult patients, to decrease the severity of increased muscle tone in elbow flexors, wrist flexors and finger flexors. Botox was subsequently approved in June of 2019 for patients ages 2 to 17 years with upper limb spasticity.

Botox is supplied as a vacuum-dried powder for reconstitution with sterile, non-preserved Sodium Chloride Injection. It is supplied as single-use 50 Unit and 100 Unit vials. Dosing of Botox for upper limb spasticity in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, or adverse event history with Botox. The recommended initial doses are as follows:
Biceps Brachii:100 - 200 Units divided in 4 sites
Flexor Carpi Radialis: 12.5 - 50 Units in 1 site
Flexor Carpi Ulnaris: 12.5 - 50 Units in 1 site
Flexor Digitorum Profundus: 30 - 50 Units in 1 site
Flexor Digitorum Sublimis: 30 - 50 Units in 1 site

The recommended dose in children per treatment session is 3 Units per kilogram to 6 Units per kilogram divided among affected muscles of the upper limb. The total dose in pediatric patients should not exceed 8 Units per kilogram body weight or 300 Units, whichever is lower, in a 3-month interval.

Clinical Results

FDA Approval
The efficacy and safety of Botox for the treatment of upper limb spasticity was evaluated in three randomized, multi-center, double-blind, placebo-controlled studies. Efficacy was measured according to the The Ashworth Scale, a clinical measure of the force required to move an extremity around a joint, with a reduction in score clinically representing a reduction in the force needed to move a joint. Possible scores range from 0 (no increase in muscle tone) to 4 (limb rigid in flexion or extension- very severe)

Study One
This trial enrolled 126 patients with upper limb spasticity who were at least 6 months post-stroke. Botox (a total dose of 200 Units to 240 Units) and placebo were injected intramuscularly into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and if necessary into the adductor pollcis and flexor pollcis longus. The subjects were followed for 12 weeks. The primary efficacy variable was wrist flexors muscle tone at week 6. The median change from baseline was -2.0 for the Botox arm compared to 0.0 for the placebo arm (p≤0.05). The median change from baseline in muscle tone for Finger Flexor was -1.0 for the Botox arm and 0.0 for the placebo arm (p≤0.05). The median change from baseline for thumb flexor muscle tone was -1.0 for both arms.

Study Two
This study compared three doses of Botox (360 Units, 180 Units or 90 Units) with placebo in 91 patients with upper limb spasticity who were at least 6 weeks post-stroke. Botox and placebo were injected into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and biceps brachii. The primary efficacy variable in Study 2 was the wrist flexor tone at Week 6. The median change from baseline was -1.5. -1.0. -1.5 for the three Botox arms (90, 180 and 360 Units) respectively and -1.0 for the placebo arm (p≤0.05). Key secondary endpoints including Physician Global Assessment, finger flexors muscle tone, and elbow flexors muscle tone were also reached.

Study Three
This study compared three doses of Botox (360, 180 or 90 Units) with placebo in 88 patients with upper limb spasticity at least 6 months post-stroke. The primary efficacy variable was wrist and elbow flexor tone. The median change from baseline on the wrist flexor muscle tone was -1.0, -1.0, -1.5 for Botox 90, 180 and 360 Units, respectively and -0.5 for placebo (p≤0.05 for Botox 360 Units vs. placebo). The median change from baseline for elbow flexor muscle tone was -0.5, -0.5 and -1.0 for the three Botox arms, respectively, and -0.5 for the placebo arm (p≤0.05 for Botox 360 Units vs. placebo). The key secondary endpoint, mean change in finger flexor tone, was also reached with statistical significance.

The FDA approval of Botox in pediatrics with upper limb spasticity was based on two trials. A placebo-controlled, double-blinded study of onabotulinumtoxinA in children 2 to 16 years of age with upper limb spasticity included 235 patients who were randomized to one intramuscular injection of onabotulinumtoxinA 3 units/kg or 6 units/kg, or placebo. Both active treatment groups demonstrated a significant reduction in Modified Ashworth Scale‐Bohannon scores compared to placebo (onabotulinumtoxinA 6 units/kg, - 1.87; onabotulinumtoxinA 3 units/kg, -1.92; P <.001). The improvement was significant at all assessments during the 12-week trial. An open-label study for upper limb spasticity included 222 subjects. This study focused on safety, with the primary outcome being the percentage of patients reporting at least one adverse event over the course of 60 weeks. The open-label trial for lower limb spasticity followed 350 participants and had the same primary outcome.

Side Effects

Adverse reactions associated with the use of Botox for upper limb spasticity may include, but are not limited to, the following:

  • pain in extremity
  • bronchitis
  • fatigue
  • nausea

Mechanism of Action

Botox for injection is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A. 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.

Literature References

McCrory P, Turner-Stokes L, Baguley IJ, De Graaff S, Katrak P, Sandanam J, Davies L, Munns M, Hughes A Botulinum toxin A for treatment of upper limb spasticity following stroke: a multi-centre randomized placebo-controlled study of the effects on quality of life and other person-centred outcomes. Journal of rehabilitation medicine : official journal of the UEMS European Board of Physical and Rehabilitation Medicine 2009 Jun;41(7):536-44

Bakheit AM, Pittock S, Moore AP, Wurker M, Otto S, Erbguth F, Coxon L A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke. European Journal of Neurology 2001 Nov;8(6):559-65

Additional Information

For additional information regarding Botox or upper limb spasticity, please visit the Botox web page.