Botox (onabotulinumtoxinA) - 4 indications

Scroll down for information on each indication:

• Brow furrow / frown lines; approved 04/01/2002
• Upper limb spasticity; approved 03/01/2010
• Chronic migraine; approved 10/01/2010
• Spasticity in pediatric patients 2 years of age and older, including those with lower limb spasticity caused by cerebral palsy; approved 07/01/2020

General Information

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 at somatic neuromuscular junctions, the parasympathetic nervous system, sympathetic preganglionic fibers (cholinergic fibers), and at some synapses in the central nervous system.

Botox is specifically indicated for the following conditions:

• Moderate to severe glabellar lines (brow furrow) in adult men and women, ages 65 and younger. 
• Upper limb spasticity in adult and pediatric patients 2 years of age and older to decrease the severity of increased muscle tone in elbow flexors, wrist flexors and finger flexors.
• The prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).
• Spasticity in pediatric patients 2 years of age and older, including those with lower limb spasticity caused by cerebral palsy.

Botox is supplied as a solution for intramuscular, intradetrusor, or intradermal administration. Please scroll down for specific dosing recommendations for each condition.

Mechanism of Action

Botox blocks neuromuscular transmission by binding to acceptor sites on motor or autonomic 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. Following intradetrusor injection, Botox affects the efferent pathways of detrusor activity via inhibition of acetylcholine release.

Side Effects

Adverse events associated with the use of Botox may include, but are not limited to, the following:

• neck pain
• headache
• worsening migraine
• muscular weakness
• eyelid ptosis
• pain in extremity
• upper respiratory tract infection

The Botox drug label comes with the following Black Box Warning: The effects of Botox and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms.

Indication 1 - Brow furrow / frown lines

approved 04/01/2002

Dosing/Administration

Botox is administered as an intramuscular injection • Glabellar Lines Administration: 0.1 mL (4 Units) into each of 5 sites, for a total dose of 20 Units (2.3) • Lateral Canthal Lines Administration: 0.1 mL (4 Units) into each of 3 sites per side (6 total injection points), for a total of 24 Units (2.3) • Forehead Lines Administration: 0.1 mL (4 Units) into each of 5 forehead line sites (20 Units) with 0.1 mL (4 Units) into each of 5 glabellar line sites (20 Units), for a recommended total of 40 Units

Clinical Trial Results

Botox was tested in a 12-month study consisting of two periods. The first period was a four-month, double-blind, placebo-controlled study of 537 patients with glabellar lines to evaluate efficacy of the drug. At day 30 following treatment, investigators' assessment of the improvement indicated that 80.2% of subjects treated with Botox showed significant reduction in severity of glabellar lines, compared to 3.0% of subjects treated with placebo showing improvement. Patients self-assessment yielded similar results.

The second treatment period was an 8-month, open-label period evaluating the safety of repeated treatments with the drug. 373 subjects from the first period continued into the second period. Of these subjects, 2.1% reported blepharoptosis (droopy eyelid) following the first treatment, and 1.2% reported this effect after a second treatment. 49% of subjects reported side effects of any type.

Indication 2 - Upper limb spasticity

approved 03/01/2010

Dosing/Administration

Botox is administered intramuscularly. 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 Trial Results

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.

Indication 3 - Chronic Migraine

approved 10/01/2010

Dosing/Administration

Botox is administered as an intramuscular injection. The recommended initial dose is 155 Units administered intramuscularly (IM) using a sterile 30-gauge, 0.5 inch needle as 0.1 mL (5 Units) injections per each site. Injections should be divided across 7 specific head/neck muscle areas: Frontalis, Corrugator, Procerus, Occipitalis, Temporalis, Trapezius, Cervical Paraspinal Muscle Group. With the exception of the procerus muscle, which should be injected at 1 site (midline), all muscles should be injected bilaterally with half the number of injection sites administered to the left, and half to the right side of the head and neck. The recommended retreatment schedule is every 12 weeks.

Clinical Trial Results

The FDA approval of Botox for chronic migraine was based on two randomized, multi-center, 24-week, 2 injection cycle, placebo-controlled double-blind studies. Both studies included chronic migraine adults who were not using any concurrent headache prophylaxis, and during a 28-day baseline period had at least 15 headache days lasting 4 hours or more, with at least 50% of these being migraine/probable migraine. In both studies, patients were randomized to receive placebo or 155 Units to 195 Units Botox injections every 12 weeks for the 2-cycle, double-blind phase. At 28 days, the efficacy data are as follows:
Study One
Change from baseline in frequency of headache days: -7.8 for Botox vs. -6.4 for placebo (p≤0.05).
Change from baseline in total cumulative hours of headache on headache days: -107 for Botox vs. -70 for placebo (p≤0.05).
Study Two
Change from baseline in frequency of headache days: -9.2 for Botox vs. -6.9 for placebo (p≤0.05).
Change from baseline in total cumulative hours of headache on headache days: -134 for Botox vs. -95 for placebo (p≤0.05).

The subjects treated with Botox had a significantly greater mean decrease from baseline in the frequency of headache days at most timepoints from Week 4 to Week 24 in Study 1 and all timepoints from Week 4 to Week 24 in Study 2 compared to placebo-treated patients.

Indication 4- Spasticity in pediatric patients 2 years of age and older, including those with lower limb spasticity caused by cerebral palsy

approved 07/01/2020

Dosing/Administration

Botox is administered intramuscularly. The recommended total dose 4 Units/kg to 8 Units/kg (maximum 300 Units) divided among affected muscles.

Clinical Trial Results

The efficacy and safety of Botox for the treatment of lower limb spasticity in pediatric patients 2 to 17 years of age was evaluated in Study 2, a randomized, multi-center, double-blind, placebo-controlled study. Study 2 included 381 pediatric patients (125 Botox 4 Units/kg, 127 Botox 8 Units/kg, and 129 placebo) with lower limb spasticity (modified Ashworth Scale ankle score of at least 2) because of cerebral palsy. A total dose of 4 Units/kg Botox (maximum 150 Units), 8 Units/kg Botox (maximum 300 Units), or placebo was injected intramuscularly and divided between the gastrocnemius, soleus, and tibialis posterior. Electromyographic guidance, nerve stimulation, or ultrasound techniques were used to assist in muscle localization for injections. Patients were followed for 12 weeks after injection. Compared to placebo, improvements in mean change from baseline for the MAS, and mean CGI score for lower limb spasticity were observed at timepoints up to Week 12 for Botox-treated patients.