Download Botox Onabotulinumtoxin A: A Meta-analysis to assess the Severity

Running head: BOTOX ONABOTULINUMTOXIN A
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Botox Onabotulinumtoxin A: A Meta-analysis to assess the Severity of Off-Label Botox usage in
Children with Cerebral Palsy
Erica Morris
Lynchburg College
Health Promotion
BOTOX ONABOTULINUMTOXIN A
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Abstract
The brand name Botox was first assigned to a batch of botulinum toxin serotype A by
Stanley
Fahn,
internationally
avowed
Doctor
of
Medicine
and
member
of
the
Psychopharmacology Advisory Committee for the Food and Drug Administration (Erbguth, 2009;
Fahn, 2016). Botulinum toxin is classified as one of the most potent toxic substances in the world.
Efficacy for the therapeutic use of botulinum toxin is based upon the premise that botulinum toxin
remains in the peripheral nervous system and is incapable of breaching the Blood-Brain Barrier
(Tenenbaum, 2016). Since receiving initial approval in 1989 botulinum toxin serotype A now also
provides short term therapeutic treatment to manage various dermatological, muscular, and chronic
pain diseases and disorders (Samuels, Correa, 2016). Allergan reveals that the greatest population
at risk for botulinum toxin diffusion are children treated for muscle spasticity (Allergan
Pharmaceuticals, 2016). Study Objective: To assess the severity of Off-Label Botox usage to treat
children. Design: Meta-analysis of 165 children treated with onabotulinumtoxin A to manage
spasticity and sialorrhoea. Methods and Measurements: The adverse events of 424 patients was
assessed in excel and SPSS. Conclusion: 75 percent of patients experienced adverse events.
Keywords: onabotulinumtoxinA, Botox for Pediatrics, onabotulinumtoxinA for cerebral
palsy
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Botox Onabotulinumtoxin A: A Meta-analysis to assess the Severity of Off-Label Botox usage in
Children with Cerebral Palsy
Clostridium botulinum
The earliest detailed report of botulism-like symptoms occurred in Wildbad, Germany
during the 18th century. Reports indicate that following the consumption of Bluzen, a popular
blood, pork, and spice sausage, thirteen individuals suffered gastrointestinal problems, double
vision, and muscle paralysis (Erbguth, 2009). The food-borne illness caused by exposure to C.
botulinum became commonly referred to as sausage poisoning. Subsequently several scientists
attributed sausage poisoning to poor sanitary conditions, undercooked, and insufficiently stored
foods (Erbguth, 2009). The term Botulism was later adopted originating from the Latin term
botulus referring to the poisonous effects of consuming sausage contaminated with
Clostridium botulinum (Erbguth, 2009). Botulism is characterized as a paralyzing disease in which
asphyxia is a common cause of death (United States Department of Agriculture Food Safety and
Inspection, 2013; Erbguth, 2009).
Initially C. botulinum was believed to only contaminate food products, however in 1931
and 1942 respectively both infant and wound botulism were discovered (Erbguth, 2009; Waseem,
M. 2017). Within the United States C. botulinum outbreaks are rare however botulism still remains
extremely fatal and therefore is of great concern for both the general public and medical
communities. Prior to 2009 25 percent of 110 botulism cases were the result of food contamination.
Recent surges of wound botulism has also been reported, and is attributed to the increase in blacktar heroin abuse (Erbguth, 2009).
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For as long as humans have preserved food for later consumption botulinum toxin
produced during vegetative cell growth of pathogen Clostridium botulinum has caused the food
borne illness (Erbguth, 2009; Albrecht, 2017). Before humans understood its method of action
Botulinum toxin worked by inhibiting the release of neurotransmitters acetylcholine,
norepinephrine, and substance P by binding to the neuromuscular synapsis on the cholinergic nerve
terminals (Al-Ghamdi, Alghanemy,Joharji, Al-Qahtani, & Alghamdi, 2015; Carraro, Trevisi, &
Martinuzzi, 2016). The inhibition of these neurotransmitters caused by botulinum toxin prevents
motor neuron stimulation and causes permanent damage to the neuron wherein a minimum of three
months must elapse for the regeneration of the neuromuscular synapsis to occur (Al-Ghamdi,
Alghanemy,Joharji, Al-Qahtani, & Alghamdi, 2015; Carraro, Trevisi, & Martinuzzi, 2016).
During the nineteenth century Belgium microbiologist Emile Pierre Marie Van Ermengem
first identified the anaerobic gram-positive bacterium C. botulinum. It was later learned that during
vegetative cell proliferation the C. botulinum bacterium produces a potent neurotoxin toxic enough
to cause illness and death in even the most minuscule amounts (Al-Ghamdi, Alghanemy, Joharji,
Al-Qahtani, & Alghamdi, 2015; Erbguth, 2009; United States Department of Agriculture Food
Safety and Inspection, 2013). The World Health Organization reports that Botulinum toxin has an
estimated effective lethal dosage of 2 nanongrams of botulinum toxin per kilogram of bodyweight
(World Health Organization, 2016).
The earliest recorded human usage of botulinum toxin discloses the use of a tasteless
powdered form of the bacterium which was intentionally extracted from contaminated blood
sausages and utilized to poison personal enemies (Erbguth, 2009). Currently the Centers for
Disease control discloses a potential threat to the United States in which aerosolized botulinum
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toxin could be used as a mechanism for a bioterrorist attack (Botulism Facts for Health Care
Providers, 2006).
Therapeutic Usage of Botulinum Toxin A
In the 1970’s Alan Scott began testing therapeutic uses for botulinum toxin to treat
strabismus of the extraocular muscles (Scott, 1981). According to Scott strabismus, also known
indiscreetly as crossed-eyes, could be safely corrected in the extraocular muscles of monkeys.
Scott’s research demonstrated that while there are obvious variations to toxicity between the
species botulinum toxin demonstrates beneficial outcomes for a patient with a condition that causes
vision problems, periodic headache and confusion ((Erbguth, 2009;Scott, 1981;Samuels, Correa,
2016;Strabismus, 2017;Samuels,Correa, 2016). Following favorable clinical trials in 1989 the
Food and Drug Administration licensed the Scott and Schantz manufacturing facilities to legally
produce and distribute botulinum toxin serotype A to the public to treat eye muscle disorders
(Erbguth, 2009).
Botox was originally termed Oculinum by Scott’s Oculinum Incorporated. Botulinum
toxin serotype A was distributed by Oculinum Incorporated until 1991 when the licensed
production of Botox was transferred completely to Allergan (Erbguth, 2009). In Adherence to
global regulatory standards for manufacturing Botox Allergan produced a batch of botulinum toxin
during the 1980’s that contained less of the neurotoxin per unit making it less likely to prompt
antibody production in patients that would render Botox ineffective (Erbguth, 2009).
The current formula of Botox® and Botox Cosmetic® is composed of active ingredient
onabotulinumtoxin A, human serum albumin, and sodium chloride (United States Patent and
Trademark Office, 2014). Concern for the current pharmaceutical composition of Botox can be
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attributed to probability of transmitting certain viruses, prions, and other infectious pathogens to
patients as result of exposure to human derived blood (Allergan Pharmaceuticals, 2016; United
States Patent and Trademark Office, 2014). However Allergan highlights in the Botox prescribing
information that human serum albumin has no immunogenicity following injection and cannot
provoke an immune response in patients (Allergan Pharmaceuticals, 2016; United States Patent
and Trademark Office, 2014). In contrast to other preparations containing botulinum toxin
onabotulinumtoxinA differs with respect to its pharmacological properties such as unit potency,
albumin content, and duration of effectiveness (Kedlaya, 2016; Drugs,FDA, 2017; Nestor, Ablon,
2011). Botox is available at strengths ranging from 50 to 100 units per vial (Kedlaya, 2016;
Drugs,FDA, 2017).
At this time Allergan is the only registered manufacturer of Botox® and Botox Cosmetic®,
however there are many distributors of the product. In 2013 the Food and Drug Administration
launched a Know Your Source: Protecting Patients from Unsafe Drugs campaign asking doctors
and other healthcare personal to verify the authenticity of their medications (FDA, 2014).
Subsequently, in 2015 both TC medical group and SB medical were fined $ 45 million and forced
to forfeit an additional $30 million dollars for smuggling misbranded unregistered Botox and other
pharmaceuticals to more than 1,300 medical practices in the United States (Centers for Drug
Evaluation and Research, 2017).
Botox® is approved to manage the symptoms of cervical dystonia, severe primary axillary
hyperhidrosis, strabismus, blepharospasm, neurogenic detrusor over-activity, chronic migraine,
and upper limb spasticity (Kedlaya, 2016). Botox Cosmetic® has also been approved to manage
moderate to severe glabellar lines, and crow’s feet (Kedlaya, 2016).
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Botox Prescribing Information
Medical personal trained to administer Botox must give special regard to the total dosage
received by each patient over time. Master Injector Dr. Craig Petry graduate of The Medical
College of Wisconsin and owner of Wyndhurst Family Medicine and Wyndhurst Medical
Aesthetics informs that tremendous volumes of onabotulinumtoxinA can produce a reaction,
however the small dosages from cosmetic usage should not warrant concern (Petry, 2017). To
administer injections healthcare personal must be trained by a medical doctor or nurse practitioner
and complete specialized training courses. Botox injections intended to manage dystonia,
spasticity, and migraine disorders are exclusively performed by a neurologist. Dr. Petry discloses
that only medical doctors can purchase legally produced Botox (Petry, 2017). Dr. Petry also
exhibits a powered form of onabotulinumtoxinA packaged in vial format that is diluted prior to
cosmetic injection (Petry, 2017). Attention to storage and handling of Botox is essential to ensure
that the highest quality of botulinum toxin is administered to patients. Licensed Medical
Aesthetician and Certified Medical Laser Technician Karen Citty instructs patients upon discharge
to reframe from placing pressure to the face for a minimum of 4 hours post injection to prevent
toxin diffusion (Citty, 2017). The injection site may also be prepared prior to Botox injection in
order to achieve optimal therapeutic outcome (Kedlaya, 2016).
Incidence of adverse effects is reported in 20 to 30 percent of patients receiving high
dosages of botulinum toxin. As a result of botulinum toxin diffusing from the injection site to the
pharyngeal muscles, dysphagia is the most common adverse event occurring in 33 percent of
patients receiving botulinum toxin for the first time (Kedlaya, 2016). Bronchitis and upper
respiratory tract infections have also occurred in patients treated for upper limb spasticity.
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Respiratory failure is also a concern of botulinum toxin diffusion (Allergan Pharmaceuticals,
2016). Urine retention has been expressed in patients treated for neurogenic detrusor over-activity
or overactive bladder (Allergan Pharmaceuticals, 2016). Reduced blinking resulting in corneal
ulcers have occurred in patients treated for blepharospasm (Allergan Pharmaceuticals, 2016).
Decreased retinal circulation resulting in vision-threatening complications has also transpired
following Botox injection for the treatment of strabismus (Allergan Pharmaceuticals, 2016).
Additional adverse events reported to the FDA include seizure, flu symptoms, muscle weakness,
and injection site reactions (Kedlaya, 2016). Complications are also indicated in patients with
neuromuscular disorders and or patients who have a compromised respiratory system (Allergan
Pharmaceuticals, 2016). According to Allergan, a patient’s total dose of Botox should not exceed
a total dosage of 360 units within a 3 month interval (Allergan Pharmaceuticals, 2016).
At Risk Populations
In 2009 as a response to adverse events associated with botulinum toxin usage the FDA
published a Botox Safety Review. The Botox Safety Review required that Allergan label their
onabotulinumtoxinA products with a Black Box warning. The Black Box Warning includes
product precaution and warning information as well as medication guidelines for the product. A
black box warning is the strongest level of warning by the FDA. The warning reports that the
effects of Botox may spread from the injection site and produce symptoms of botulism in patients
which can become fatal (Allergan Pharmaceuticals, 2016; Samuels, Correa, 2016). Additionally
the review further distinguished the names for each botulinum toxin containing product. These
names infer that the various products containing botulinum toxin are not interchangeable. These
products also possess different pharmacological properties. Physicians may prescribe prescription
drugs for uses other than those approved by the FDA. Such use is termed as off-label usage. Off-
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label uses of Botox include: dystonia, hemi facial spasms, and cerebral palsy in children. Within
the highlights of prescribing information Allergan reveals that the greatest population at risk for
botulinum toxin diffusion are children treated for muscle spasticity (Allergan Pharmaceuticals,
2016). The purpose of this study is to assess the severity of off-label onabotulinumtoxinA usage
in children treated to manage diseases and disorders associated with cerebral palsy.
Study Methods.
A PubMed, Google Scholar, and Cochrane Library search was performed using the
keywords onabotulinumtoxinA, Botox for pediatrics, and onabotulinumtoxinA for cerebral palsy.
The P.I.C.O. method was used to determine the inclusion and exclusion criteria for the metaanalysis. Articles in full English text published between 2010, one year following the safety review,
and 2017 were included in the meta-analysis. Articles were also included in the study if the patients
were children receiving Botox interventions for spasticity or sialorrhoea. This meta-analysis
includes articles with Botulinum toxin A interventions for children with cerebral palsy, a
retrospective chart review, and a randomized double-blind placebo-controlled study.
Table 1. Patient Demographics, 2011-2016
Study
No. of
Patients
Treated w.
Botox
Average Age
Male :
Female
Edwards et al.,2015
41
23
7
16:7
Fattal-Valevski, Sagi, Domenievitz,2011
30
30
9.9
16:14
Koman et al., 2013
71
28
9
24:63
Lin, Huang,Lin,Shieh,Chung,Chen,2015
12
12
7.6
4:8
Montgomery et al.,2016
274
76
7.3
176:98
Total
424
165
Source: PubMed Medline, Google Scholar, Cochrane Library
8.16 yrs.
47: 50
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Twenty articles were independently selected by one reviewer. Links to the articles were
pooled into a word document and a second reviewer made independent selections from the pooled
articles. The second reviewer determined from the pooled articles which articles met the inclusionexclusion criteria by visiting the links and reading the abstracts of each article. A final selection
was reached by consensus utilizing inclusion-exclusion and relevancy criteria. Data was collected
and entered by both reviewers by consensus. The primary parameter utilized to assess severity was
mean injection and adverse events.
Table 2. Weight and Description of Treatment, 2011-2016
Study
Weight
Edwards et al.,2015
51.5
Lin, Huang,Lin,Shieh,Chung,Chen,2015
Mean Unit Dose
10.5
400
50
127
75
13.1
366
45.75
10
218
57.41 lbs.*
20.9 units*
277.75*
Fattal-Valevski, Sagi, Domenievitz,2011
Koman et al., 2013
Mean Injection
Montgomery et al.,2016
Total
Source: PubMed Medline, Google Scholar, Cochrane Library *Averages influenced by unrepresented
data.
If studies failed to report data the averages were calculated without the value. The quality
of articles included in the meta-analysis was assessed based on relevant information, peer-review,
and professionally conducted medical research. Reference lists of the articles returned from the
search were perused to identify relevant articles.
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Table 3. Treatment Details, 2011-2016
Study
Patient Retention
Treatment
Duration
Adverse Event
Edwards et al.,2015
37
4 mons
Fattal-Valevski, Sagi, Domenievitz,2011
26
3-4 mons
Koman et al., 2013
36
6.5 mons
Lin, Huang,Lin,Shieh,Chung,Chen,2015
12
9 mons
0
Montgomery et al.,2016
208
4 mons
17
Total
319
78
69
124
Source: PubMed Medline, Google Scholar, Cochrane Library
Excluded from the meta-analysis were articles focused on treatment methods and
ultrasound characterization of muscles. All Articles that were not peer-reviewed were not included
in the meta-analysis. Any articles not meeting the inclusion criteria for the meta-analysis were
excluded.
Statistical Analysis
A sample size of 424 patients were analyzed to identify the number of patients treated with
Botox. An average of the mean age of patients was calculated. The sample population was further
analyzed to identify gender distribution. An average of the mean age was calculated as well as
mean weight, injection, and unit dosage. Total adverse events as result of Botox usage was
calculated. Among the patients receiving Botox injections percentages of adverse events was
calculated. A Pearson’s correlations test was performed in SPSS to determine if there was a
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correlation between weight and adverse events. Significance between treatment and adverse event
was also analyzed in SPSS.
Results
Of the 424 patients 165 patients who received Botox treatment. From the 5 articles the
average age calculated as 8 years old. The sample population of 424 patients displayed equal
distribution between the sexes within the study. For each study the average weight, injection, and
unit dose was 57.41 pounds, 20.9 units, and 277.75 units respectively. However calculations were
effected by unreported data. Among patients receiving Botox treatments there were a total of 124
adverse events ranging from moderate to severe symptoms. A Pearson’s Correlations test revealed
that there was no significance between weight and adverse event by the extrapolation of r=0.04
and p=0.975. There was also no correlation between treatment time and adverse event based on
r=-.665 and p=.335 as result of unreported data from the articles. Of the 165 patients treated with
Botox 75 percent experienced a moderate to severe adverse event.
Table 4. Correlation to Test Weight and Adverse Event
Mean Weight
Pearson Correlation
Mean Weight
Adverse Event
1
.040
Sig. (2-tailed)
N
Adverse Event
.975
3
3
Pearson Correlation
.040
1
Sig. (2-tailed)
.975
N
3
4
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Table 5. Correlations to Test Treatment Duration and Adverse Event
Adverse Event
Adverse Event
Pearson Correlation
1
Sig. (2-tailed)
N
Treatment time
Pearson Correlation
Sig. (2-tailed)
N
Treatment time
-.665
.335
4
4
-.665
1
.335
4
Conclusion
Through clinical trials have demonstrated the efficacy for therapeutic Botox treatment in
adults concern should be utilized for the off-label usage specifically in children. Off-label usage
of botulinum toxin can expose children to dosages exceeding the 360 units per month advised by
Allergan (Allergan Pharmaceuticals, 2016; Samuels, Correa, 2016). Based on the primary
assessment of severity majority of the children administered Botox experienced an adverse
reaction. However none of the articles reported life-threatening complications. The prognosis for
cerebral palsy is a normal life expectancy however muscles effected by the disease can become
stiff, spastic, and develop contractures. Contractures can lead to bone deformation. It should be
noted that more research needs to be conducted to determine the severity of off-label use of Botox
in children.
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Recommendations

Utilize Botox only for uses Approved by the Food and Drug Administration

Do not exceed 360 units of botulinum toxin in a 3 month interval

Do not use Botox treatment if you are pregnant or intend to become pregnant

Certain muscle conditions can increase risk of complications; do not use Botox if you have
muscular or nerve disorders.

The efficacy of Botox treatment has not been established in children younger than 2 years old,
therefore reframe from treatment in children of the age.

Effects of Botox may be potentiated by aminoglycosides and other neuromuscular transmission
agents such as muscle relaxants. In such cases do not combine Botox treatment.

Lastly Botox should only and always be administrated by a licensed medical professional
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References
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