Botulinum toxins have traditionally been associated with foodborne diseases, but medically there has been much interest in the ability of the toxins to block neuromuscular conduction. Botulinum toxin is a neurotoxin derived from the organism Clostridium botulinum (C. botulinum). The seven distinct neurotoxins (A, B, C, D, E, F, G) produced from C. botulinum differ in their binding and pharmacologic activity, but they all exhibit a similar molecular structure and share primarily the same mechanism of action: the inhibition of acetylcholine release at the neuromuscular junction.
The blocking of neuromuscular conduction is believed to be a three-step process: (1) extracellular binding of the toxin with the presynaptic site of the neuromuscular junction; (2) internalization and release of the toxin into the cytosol of the nerve terminals; and (3) ultimate inhibition of acetylcholine release from the nerve terminals. The resulting decrease of contractility, strength, and tension of certain muscle groups may improve clinical outcomes in individuals who have diseases associated with inappropriate or exaggerated muscle contractions.
Currently, five US Food and Drug Administration (FDA)-approved botulinum toxin products are available in the United States:
- OnabotulinumtoxinA (Allergan) (Botox and Botox Cosmetic)
- PrabotulinumtoxinA-xvfs (Jeuveau)
- RimabotulinumtoxinB (Solstice Neurosciences, Inc.) (Myobloc)
- AbobotulinumtoxinA (Ipsen Biopharmaceuticals) (Dysport)
- IncobotulinumtoxinA (Merz Pharmaceuticals, Raleigh, NC) (Xeomin)
- LetibotulinumtoxinA-wlbg (Croma Pharma; Hugel) (Letybo)
- DaxibotulinumtoxinA-lanm (Revance Therapeutics, Inc.
Newark, CA) (Daxxify)
These products are distinct and are not interchangeable with other botulinum toxin agents; thus, the units of each product cannot be compared or converted into units of another botulinum toxin product.
The FDA-approved uses of these products are as follows:
- Axillary hyperhidrosis, primary (severe underarm sweating):
- OnabotulinumtoxinA (Botox)
- Blepharospasm (abnormal tics and twitches of the eyelids):
- OnabotulinumtoxinA (Botox) in those ages 12 years and older
- IncobotulinumtoxinA (Xeomin) in adults previously treated with onabotulinumtoxinA (Botox)
- Cervical dystonia (CD; a condition that affects the muscles in the neck that control the position of the head):
- OnabotulinumtoxinA (Botox)
- AbobotulinumtoxinA (Dysport)
- RimabotulinumtoxinB (Myobloc)
- IncobotulinumtoxinA (Xeomin) (botulinum toxin–naïve and previously treated individuals)
- DaxibotulinumtoxinA-lanm (Daxxify)
- Forehead lines associated with frontalis muscle activity (to temporarily improve the appearance):
- OnabotulinumtoxinA (Botox Cosmetic)
- Glabellar lines (to temporarily improve the appearance of frown lines between the eyebrows):
- OnabotulinumtoxinA (Botox Cosmetic)
- AbobotulinumtoxinA (Dysport)
- PrabotulinumtoxinA-xvfs (Jeuveau)
- IncobotulinumtoxinA (Xeomin)
- DaxibotulinumtoxinA-lanm (Daxxify)
- Lateral canthal lines (crow's feet) associated with orbicularis oculi activity (to temporarily improve the appearance):
- OnabotulinumtoxinA (Botox Cosmetic)
- Migraine, chronic:
- OnabotulinumtoxinA (Botox)
- Overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency:
- OnabotulinumtoxinA (Botox)
- Sialorrhea, chronic, in individuals 2 years of age and older:
- IncobotulinumtoxinA (Xeomin)
- Sialorrhea, chronic, in adults:
- RimabotulinumtoxinB (Myobloc)
- Spasticity of upper limb in adults:
- IncobotulinumtoxinA (Xeomin)
- Spasticity of upper and lower limbs in children 2 years of age and older and adults:
- OnabotulinumtoxinA (Botox)
- AbobotulinumtoxinA (Dysport)
- Strabismus (crossed eyes):
- OnabotulinumtoxinA (Botox) in those ages 12 years and older
- Urinary incontinence due to neurogenic bladder:
- OnabotulinumtoxinA (Botox)
The FDA has issued an import alert stating that "only botulinum toxin manufactured under US license and bearing the US license number on its labeling may be imported into the United States unless the unlicensed version has an Investigational New Drug (IND) application accepted by the Center for Drug Evaluation and Research."
OnabotulinumtoxinA (Botox and Botox Cosmetic) block neuromuscular transmission by cleaving synaptosomal-associated protein (SNAP)-25, a protein responsible for the release of acetylcholine from nerve endings. This, in turn, produces a decrease in chemical muscle denervation, resulting in reduced muscular contractions. Similarly, rimabotulinumtoxinB (Myobloc) and abobotulinumtoxinA (Dysport) use a mechanism of like action to inhibit the release of acetylcholine.
RimabotulinumtoxinB (Myobloc) is a purified neurotoxin that acts at the neuromuscular junction to produce flaccid paralysis. The neurotoxin is produced by fermentation of the bacterium C. botulinum type B (Bean strain) and exists in noncovalent association with hemagglutinin and nonhemagglutinin proteins as a neurotoxin complex.
DaxibotulinumtoxinA-lanm is an acetylcholine release inhibitor and neuromuscular blocking agent.
DaxibotulinumtoxinA-lanm is a 150-kDa botulinum toxin without accessory proteins purified from the
bacterium C. botulinum type A.
On August 11, 2023, the FDA approved Revance Therapeutics’ Daxxify (daxibotulinumtoxinA-Ianm) for the treatment of CD in adult individuals. Daxxify was previously approved on September 7, 2022, for the temporary improvement in the appearance of moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity in adult individuals. Approval for Daxxify’s label expansion for CD was based on data from the Phase 3 ASPEN clinical program (ASPEN-1 and ASPEN open-label study [OLS]), which included 382 individuals with moderate-to-severe CD. In ASPEN-1, individuals received a single low dose of Daxxify (125 units), a high dose of Daxxify (250 units), or a placebo. ASPEN-1 met its primary endpoint, a mean change from baseline on the Toronto Western Spasmodic Torticollis Rating Scale at Weeks 4 and 6. The low-dose group showed a reduction from baseline of 12.7 points and the high-dose group showed a reduction of 10.9 points compared to a 4.3-point reduction for the placebo group. The median duration of effect was 24.0 weeks for the low-dose group and 20.3 weeks for the high-dose group. In ASPEN-OLS, symptoms continued to improve with successive Daxxify treatments at doses of up to 300 units, while adverse events remained low. The recommended dose of Daxxify for CD is 125 to 250 units given via intramuscular injection as a divided dose among affected muscles.
On February 10, 2021, the FDA approved onabotulinumtoxinA (Botox) for the treatment of pediatric individuals for detrusor overactivity associated with a neurologic condition. The safety and efficacy of onabotulinumtoxinA were evaluated in a multicenter, randomized, double-blind, parallel-group clinical study conducted in individuals from 5 to 17 years of age with urinary incontinence due to detrusor overactivity associated with a neurologic condition and using clean intermittent catheterization. A total of 113 individuals (including 99 with spinal dysraphism such as spina bifida, 13 with spinal cord injury, and one with transverse myelitis) who had an inadequate response to or were intolerant of at least one anticholinergic medication were enrolled. These individuals were randomly assigned to 50 Units, 100 Units, or 200 Units, not to exceed 6 Units/kg body weight. The study results demonstrated within group improvements in the primary efficacy variable of change from baseline in daytime urinary incontinence episodes (normalized to 12 hours) at the primary efficacy time point (week 6) for all three Botox treatment groups. Botox 200 Units showed an additional reduction in maximum bladder pressure when compared to 50 Units. The most common adverse reactions in the studies were bacteriuria (20%), urinary tract infection (7%), leukocyturia (7%), and hematuria (3%).
On December 18, 2020, the FDA approved IncobotulinumtoxinA (Xeomin) for the treatment of pediatric individuals (from 2 to 17 years of age) with chronic sialorrhea. The efficacy and safety of Xeomin were evaluated in a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial that enrolled and treated a total of 216 pediatric individuals from 6 to 17 years of age with chronic sialorrhea associated with cerebral palsy (CP), other genetic or congenital disorders, or traumatic brain injury. An additional 35 individuals, from 2 to 5 years of age, were treated with open-label Xeomin in the study. The co-primary endpoints among individuals age 6 to 17 years were defined as the change in unstimulated salivary flow rate (uSFR) from baseline to week 4 and the Global Impression of Change Scale (GICS) score from baseline to week 4, representing the functional improvement in drooling, as assessed by the caregiver. Xeomin demonstrated significantly reduced uSFR and improved GICS versus placebo at week 4 among individuals age 6 to 17 years, and sustained efficacy over 64 weeks. Improvement in chronic sialorrhea increased with each injection cycle in comparison to the baseline. GICS scores were comparable among individuals ages 2 to 5 years, who received Xeomin treatment and not placebo throughout the study. No individuals demonstrated clinical resistance or secondary treatment failure due to neutralizing antibodies (Nab), supporting the importance of Xeomin’s unique purification process through XTRACT technology. The most common adverse reactions affecting 1% or more of individuals were bronchitis, headache, and nausea/vomiting. The most common adverse reaction affecting individuals age 2 to 5 years was nasopharyngitis.
On October 24, 2019, the FDA approved onabotulinumtoxinA (Botox) for the treatment of pediatric individuals from 2 to 17 years of age with lower limb spasticity. The efficacy and safety of Botox for the treatment of lower limb spasticity in pediatric individuals was evaluated in a randomized, multicenter, double-blind, placebo-controlled study that included 381 pediatric individuals (125 received 4 Units/kg [maximum 150 Units], 127 received eight Units/kg [maximum 300 Units], and 129 received placebo) with lower limb spasticity (Modified Ashworth Scale [MAS] ankle score of at least 2). Individuals were followed up for 12 weeks after injection. The primary efficacy endpoint was average change of spasticity in S score (ankle) at weeks 4 and 6. Secondary efficacy endpoints included clinical global impression (CGI [scales that measure symptom severity, treatment response, and the efficacy of treatments]), Modified Tardieu Scale (MTS; identifies the point in the muscle's range where spasticity is occurring), goal attainment scale** (GAS), and measures of gait. Safety and tolerability of treatments were also assessed. Botox decreased spasticity average S score at weeks 4 and 6 by 1.1 in 8 U/kg group and by 1.0 in 4 U/kg group; both doses were significantly superior to placebo (−0.8; P<0.05). Botox dose of 8 U/kg significantly improved CGI by 1.6 versus placebo (1.4; P=0.023); Botox dose of 4 U/kg, 1.5 (P=0.229 vs placebo). Both Botox groups significantly improved active and passive GAS versus placebo; Botox dose of 8 U/kg significantly improved measures of gait versus placebo. Rates of individuals reporting one or more adverse event (AE) were similar across treatment groups: Botox, 43.3 percent (n=110); placebo, 49.2 percent (n=63). Serious AEs were reported by 1.2 percent (n=3) and 3.1 percent (n=4), respectively. No new safety concerns were identified. On September 25, 2019, the FDA expanded the use of abobotulinumtoxinA (Dysport) to include the treatment of upper limb spasticity in pediatric individuals 2 years of age and older.
The efficacy and safety of abobotulinumtoxinA (Dysport) for the treatment of upper limb spasticity in children with CP was evaluated in a phase III, multicenter, double-blind, prospective, randomized, low-dose controlled, multiple treatment study. A total of 208 botulinum toxin naïve or non-naïve (66 percent had prior treatment with a botulinum toxin) individuals weighing at least 10 kg, with a baseline MAS* of grade 2 or greater at the primary targeted muscle groups (PTMG), were enrolled in the modified intention to treat population (mITT). Individuals received Dysport at the following doses: (16 Units/kg up to maximum of 640 U [n=70] ), Dysport (8 Units/kg up to maximum of 320 U [n=69] ), or Dysport (2 Units/kg [n=69] ) injected into the upper limb. The elbow flexors and wrist flexors respectively were the PTMG in 57 percent and in 43 percent of individuals.
The primary efficacy endpoint was the mean change from baseline in MAS* in the PTMG at week 6. The secondary efficacy endpoint was the mean Physician Global Assessment (PGA)*** score assessed at week 6. AbobotulinumtoxinA (Dysport) demonstrated statistically significant improvements from baseline at week 6 with doses of 8 Units/kg and 16 Units/kg, as measured by the MAS* in the elbow or wrist flexors. The most common adverse reactions (>10 percent) in pediatric individuals with upper limb spasticity for Dysport were upper respiratory tract infection and pharyngitis.
On June 21, 2019, the FDA approved onabotulinumtoxinA (Botox) for the treatment of pediatric individuals from 2 to 17 years of age with upper limb spasticity. The approval for upper limb spasticity was based on a randomized, multicenter, double-blind, placebo-controlled study (NCT01249417 ) that included 234 pediatric individuals, who received the following doses: 78 individuals received Botox 3 Units/kg, 77 received Botox 6 Units/kg [maximum 200 Units], and 79 received placebo) with upper limb spasticity (MAS* elbow or wrist score of at least 2) because of CP or stroke. Individuals were followed for 12 weeks after injection. Primary endpoints were the average of the change from baseline in MAS* principal muscle group score (elbow or wrist) at week 4 and week 6, and the average of the Clinical Global Impression of Overall CGI at week 4 and week 6. The CGI evaluated the response to treatment in terms of how the individual was doing in their life using a nine-point scale (minus 4=very marked worsening to plus 4=very marked improvement). Compared to placebo, significant improvements in MAS* change from baseline were observed at all time points for Botox-treated individuals. The CGI scores numerically favored Botox over placebo, but the difference was not statistically significant.
In July 2016, the FDA approved Dysport for lower limb spasticity in pediatric individuals. The safety and efficacy of Dysport for the treatment of lower limb spasticity due to CP causing dynamic equinus foot deformity in pediatric individuals from 2 to 17 years of age was evaluated in a double-blind, placebo-controlled, multicenter study. A total of 235 (158 Dysport and 77 placebo) toxin-naïve or non-naïve individuals within MAS* of grade 2 or greater at the ankle plantar flexors were enrolled to receive Dysport at the following doses: 10 Units/kg/leg (n=79), Dysport 15 Units/kg/leg (n=79), or placebo (n=77) injected into the gastrocnemius and soleus muscles. Forty-one percent of individuals (n=66) were treated bilaterally and received a total lower limb Dysport dose of either 20 Units/kg (n=37) or 30 Units/kg (n=29). The primary efficacy endpoint was the mean change from baseline in MAS* in ankle plantar flexor at week four; a co-primary endpoint was the mean Physician’s Global Assessment (PGA)*** score at week four. Study results showed an improvement in Dysport group versus placebo on muscle tone at both doses at week 4 postinjection (Primary endpoint – Assessment scale: MAS)*. The Physician’s Global Assessment treatment differences versus placebo were also significant. The most frequent treatment emergent adverse events were common childhood infections (upper respiratory tract infections).
On October 15, 2010, the FDA approved onabotulinumtoxinA (Botox) for prophylaxis of headaches in adults with chronic migraine headache (at least 15 days per month with headache lasting at least 4 hours per day). The approval for chronic migraine was based on results of the phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) program, which consisted of two double-blind, placebo-controlled clinical trials that included 1384 adults from 122 centers in North America and Europe. In both of these studies, individuals receiving onabotulinumtoxinA (Botox) had a significantly greater decrease in the frequency of headache days from baseline compared with placebo at 24 weeks: 7.8 and 9.2 fewer days for the treated groups versus 6.4 and 6.9 days for the placebo groups, respectively. Treated individuals also had a total cumulative reduction in headache hours by 107 and 134 hours, respectively, compared with 70 and 95 hours for the placebo groups.
On April 29, 2009, abobotulinumtoxinA (Dysport) was approved by the FDA for the treatment of CD. AbobotulinumtoxinA (Dysport) was evaluated in two randomized, double-blind, placebo-controlled, single-dose, parallel group studies in treatment-naïve CD individuals. A total of 252 individuals were enrolled. The primary assessment of efficacy was based on the total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) change from baseline at week 4 for both studies. The scale evaluates the severity of dystonia, individual perceived disability from dystonia, and pain. The adjusted mean change from baseline in the TWSTRS total score was statistically significantly greater for the abobotulinumtoxinA (Dysport) group than the placebo group at weeks 4 in both studies.
On December 8, 2000, the FDA approved rimabotulinumtoxinB (Myobloc) for the treatment of CD. The approval for CD was based on two phase III, randomized, multicenter, doubleblind, placebo-controlled studies. Both studies enrolled only adult individuals who had a history of receiving botulinum toxin type A. Study #301 enrolled individuals who were perceived as having an acceptable response to type A toxin, while Study #302 enrolled only individuals who had secondarily lost responsiveness to type A toxin. Study #301 enrolled 109 individuals, and 77 individuals were enrolled into Study #302. Individual evaluations continued for 16 weeks postinjection. The primary efficacy outcome variable for both studies was the TWSTRS Total Score (scale range of possible scores, 0–87) at week 4. The secondary endpoints were the Individuals Global and PGA of change at Week 4. TWSTRS Total Score at week 4 and Patient Global Assessment among subgroups by gender or age showed consistent treatment-associated effects across these subgroups.
*MAS score measures resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. Scoring: 0=No increase in muscle tone to 4=Affected part(s) rigid in flexion or extension.**The GAS is a functional five-point scale used to measure progress toward individual therapy goals.
***The Physician Global Assessment (PGA) is a five- or six-point scoring system used to assess disease severity.
COSMETIC SERVICES
Cosmetic services are those provided to improve an individual's physical appearance, from which no significant improvement in physiologic function can be expected. Emotional and/or psychological improvement alone does not constitute improvement in physiologic function.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issues by leading professional organizations and government entities.
