BOTOX APPLICATIONS.pdf

Manuscript Number:

Title: Application of Botulinum Toxin to Clinical Therapy, Advances and Cautions Short Title: Application of Botulinum Toxin

Article Type: Therapeutic Review

Keywords: Botox®; OnabotulinumtoxinA; Botulinum toxin type A;

Botox Cosmetic®; Dysport®; AbobotulinumtoxinA; Myobloc®; RimabotulinumtoxinB; Botulinum toxin type B;

therapy; pain management; cosmesis; anal fissure; strabismus; Cervical dystonia; Severe primary axillary hyperhidrosis; Blepharospasm; glabellar lines;

Cervical dystonia

Corresponding Author: DR/ NORMAN S. LEVY, M.D., Ph. D.

Corresponding Author's Institution: FLORIDA OPHTHALMIC INSTITUTE First Author: NORMAN S. LEVY, M.D., Ph. D.

Order of Authors: NORMAN S. LEVY, M.D., Ph. D.; DAVID T LOWENTHAL, MD, PHD Manuscript Region of Origin: UNITED STATES

Abstract: The therapeutic use of botulinum toxin type A (BoNT-A) has followed a novel and

unanticipated pathway of applications, from its initial application by Scott to paralyze the extraocular muscles of the eyes to correct strabismus. In the late 1970s, Scott formed a company, called Oculinum Inc, to make BoNT-A available for this ophthalmic application. From this modest and limited beginning, it has found utility for treatment of a plethora of cosmetic, neuromuscular and skeletal disabilities, including cervical dystonia, blepharospasm and the temporary improvement in the appearance of moderate-to-severe glabellar lines. BoNT-A is now being used as therapy in voiding disorders, migraine and tension-type headache, writer's cramp, and laryngeal muscle hyperactivity syndromes. It has reduced the spasm and pain associated with perianal fissures. It has found application in the reduction of glandular function in severe primary axillary hyperhidrosis and sialorrhea. Additional applications are being studied in the area of pain management.

Seven different antigenic botulinum toxins are produced by the different strains of C. botulinum (types A-G). Botulinum toxin type A was the first developed for therapeutic use. Botulinum toxin type B was recently approved by the FDA for some limited indications. Types C and F are undergoing clinical evaluation. These antigenically distinct moieties have differing durations of action.

The FDA has recently required the updating of the prescribing information for onabotulinumtoxinA (marketed as Botox®/Botox Cosmetic®), abobotulinumtoxinA (marketed as Dysport®) and

FLORIDA OPHTHALMIC INSTITUTE Diseases and Surgery of the Eye NORMAN S. LEVY, M.D., PH.D.

7106 N.W. 11th Place-Suite B, Gainesville, Florida 32605-3192 Telephone (352) 331-2020

FAX (352) 331-2019 Telephone (386) 752-7406 E-mail: [email protected]

May 20, 2010

John Somberg, M. D., Editor in Chief

American J. of Therapeutics

http://www.editorialmanager.com/ajt/mainpage.html

Re:

Dear Dr. Somberg:

Along with my colleague, David T. Lowenthal, M. D., Ph. D., I have revised a

therapeutic review for consideration in your Journal in the section, Novel Drug Use.

There are no conflicts of interest. Neither Dr. Lowenthal nor I have any material interest

in any of the companies associated with the development or manufacturing of botulinum

products. Neither of us consult for any company associated with these products. Dr.

Levy has done clinical research of glaucoma products for Allergan in the past.

This paper did not involve the use of any patients or subjects. Figures were provided

courtesy of Allergan, Incorporated and no release was required.

It is our hope that it will be of interest to the Journal and your readers.

Sincerely,

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1

Application of Botulinum Toxin to Clinical Therapy, Advances and Cautions

Norman S. Levy, M.D., Ph.D.* and David T. Lowenthal, M. D., Ph. D.**

* Florida Ophthalmic Institute, 7106 N. W. 11th Place, Gainesville, Fl 32605

**Consulting Clinical Pharmacologist, Dept. of Medicine, University of Florida, Gainesville, Fl 32601. Reprint requests to Dr. Levy.

ABSTRACT

The therapeutic use of botulinum toxin type A (BoNT-A) has followed a novel and unanticipated pathway of applications, from its initial application by Scott to paralyze the extraocular muscles of the eyes to correct strabismus. In the late 1970s, Scott formed a company, called Oculinum Inc, to make BoNT-A available for this ophthalmic application. From this modest and limited beginning, it has found utility for treatment of a plethora of cosmetic, neuromuscular and skeletal disabilities, including cervical dystonia, blepharospasm and the temporary improvement in the appearance of moderate-to-severe glabellar lines. BoNT-A is now being used as therapy in voiding disorders, migraine and tension-type headache, writer's cramp, and laryngeal muscle hyperactivity syndromes. It has reduced the spasm and pain associated with perianal fissures. It has found application in the reduction of glandular function in severe primary axillary hyperhidrosis and sialorrhea. Additional applications are being studied in the area of pain management, based upon its apparent ability to inhibit neuropeptide release from nociceptors.

Seven different antigenic botulinum toxins are produced by the different strains of C. botulinum (types A–G). Botulinum toxin type A was the first developed for therapeutic use and approved by the FDA. Botulinum toxin type B was recently approved by the FDA for some limited indications. Types C and F are undergoing clinical evaluation. The mechanism of action of these antigenically distinct moieties is similar, but the duration of action varies.

The FDA has recently required the updating of the prescribing information for onabotulinumtoxinA (marketed as Botox®/Botox Cosmetic®), abobotulinumtoxinA (marketed as Dysport®) and rimabotulinumtoxinB (marketed as Myobloc®) to ensure their continued safe use. These products are FDA approved for specific indications. The FDA is urging healthcare professionals and patients to report side effects from their use to the FDA’s Adverse Event Reporting program.

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Application of Botulinum Toxin to Clinical Therapy

The therapeutic use of botulinum toxin type A (BoNT-A) has followed an unanticipated path, from its initial application for strabismus therapy to the plethora of cosmetic, neuromuscular and skeletal disabilities for which it is now used. Seven different antigenic botulinum toxins are produced by the different strains of Clostridium botulinum (types A–G).1 BoNT-A was the first developed for therapeutic use and approved by the FDA.2 OnabotulinumtoxinA protein (marketed as Botox®/Botox Cosmetic®) contains low concentrations of the highly purified BoNT-A.3 This product is administered by injection to reduce specific muscle or glandular activity for an extended period.4 Botulinum toxin type B has recently been approved for specific indications by the FDA.5 Types C and F are undergoing clinical evaluation.

Botulism

The ingestion (or injection) of botulinum toxin can produce symptoms of a serious nature. The symptoms of botulism include loss of strength and diffuse muscle weakness, double vision, blurred vision, drooping eyelids, dysphonia, dysarthria, dysphagia, urinary

incontinence, and dyspnea due to paralysis of the respiratory muscles.6 The latter can lead to death.7

The clinical disease entity of botulism had been well described by the early 19th century. However, it was not until 1895 that the bacterium C. botulinum was identified as its causal source by van Ermengem.8 By the 1920s, BoNT-A was isolated in purified form as a stable acid precipitate by Sommer at the University of California, San Francisco.9

Biologic Warfare

Further research into its chemical structure and purification was supported by governmental agencies interested in its potential as an instrument of biologic warfare.10 In 1946, Schantz and colleagues succeeded in purifying BoNT-A in crystalline form, providing scientists with the raw material necessary to study the molecule in greater detail.11

Research and Understanding

Studies in the ensuing decade characterized the physiologic actions of BoNT-A. Brooks demonstrated that it blocked the release of acetylcholine from motor nerve endings, thereby inducing a temporary reduction in muscle activity.12 Levy demonstrated the effects of BoNT-A on the transmembrane potentials of dispersed, cultured, chick embryo heart cells.13

Mechanism of Action

Motor nerves produce muscle contraction by releasing the neurotransmitter acetylcholine, which is stored in vesicles in the cytoplasm. The vesicles must fuse with the cell membrane for the acetylcholine to be released.The membrane protein that enables the attachment of the vesicles to the cell membrane is called SNAP-25.

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(Fig. 2). 15,16 Therein, the light chain is activated. The light chain is a zinc-dependent metalloprotease that cleaves the SNAP-25 protein.This interferes with the necessary attachment of the acetylcholine containing vesicles to the cell membrane (Fig. 3). Thus, without attachment, there is no release of acetylcholine into the neuromuscular junction and no muscle contraction.17

A single administration of BoNT-A can last from weeks to months. The duration of the blockage depends on the individual patient, the method and amount of BoNT-A administered. When a nerve ending is blocked, new nerves sprout toward the inactive muscle, renewing its ability to effect contractions (Fig. 4). After an extended interval, the original nerve endings regain their function and the newly appearing nerve sprouts disappear.18

Botulinum Toxin Therapy and the Eye

In the early 1970s, Scott, working at the Smith-Kettlewell Eye Research Foundation in San Francisco, studied BoNT-A as an alternative to surgery for strabismus.19 Scott was able to realign crossed eyes by injecting a small amount of BoNT-A into the extraocular muscles of monkeys with strabismus.20 He collaborated with Schantz to develop BoNT-A for human treatment of strabismus.21-22 Subsequently, he formed a company, called Oculinum Inc, to provide this product for ophthalmic applications.23-24

Botulinum Toxin Therapy for Neuromuscular and Skeletal Disabilities

In 1988, Allergan, Inc. acquired the rights to distribute BoNT-A and, the following year, received approval from the FDA to market BoNT-A for the treatment of strabismus and blepharospasm in patients over 11 years of age.25 Allergan changed the product’s name to Botox®.

Research over the next two decades expanded the indications for BoNT-A to include treatment of the abnormal head position and neck pain associated with cervical dystonia in adults.26 The medical indications were further expanded in 2002 to include a cosmetic indication, the temporary improvement of moderate-to-severe frown lines between the eyebrows (glabellar lines) in adults younger than 65 years of age.27 For this new indication, Allergan marketed the product as Botox® Cosmetic (onabotulinumtoxinA) in the United States.28 In July 2004, Botox® was approved to treat severe primary axillary hyperhidrosis when topical medicines are ineffective.29 Additional applications in the area of pain management have been evaluated, based upon the apparent ability of this neurotoxin to inhibit neuropeptide release from nociceptors.1 BoNT-A is also being studied for therapy for voiding disorders, perianal fissures, migraine and tension-type headache, writer's cramp, sialorrhea, and laryngeal muscle hyperactivity syndromes and many other conditions. 30-31

New botulinum toxin pharmaceuticals have been developed for clinical use. Table 1 lists the established names, name changes and the approved indications for each product.

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Physician Training and Administration

BoNT-A is a remarkably safe drug with relatively few adverse effects at therapeutic doses. The most common adverse effects are muscle weakness, fatigue, flu-like symptoms, dry mouth, dizziness and skin rash.However, all the serious adverse effects of botulism may also occur and it is imperative that physicians employing this treatment be thoroughly familiar with these adverse reactions.33-35 Errors in placement of the injection can result in damage to the target or adjacent tissues.36 The physician must be capable of evaluating the presence of an adverse event and provide prompt and appropriate treatment. The informed consenting process must alert patients to the possibility of the known adverse effects associated with its administration. These products should only be used by a physician, who both has an

understanding of their mechanism of action and clinical experience in their administration. Use of a non–FDA-approved botulinum product can have significant consequences.37

On July 31, 2009, FDA approved the following revisions to the prescribing information of Botox

®

®

®

 A Boxed Warning has been added to the prescribing information to highlight that botulinum toxin may spread from the area of local injection to produce life-threatening distant spread of toxin to cause botulism.

 A Risk, Evaluation and Mitigation Strategy (REMS) that includes a Medication Guide to help patients understand the risks and benefits of botulinum toxin products.  Changes to the established drug names to reinforce individual potencies and prevent

medication errors. The potency units are specific to each botulinum toxin product and doses cannot be converted among products. There is no interchangeability among products.

Physicians need to:

 Appreciate that, at the approved doses, no definitive reports of serious adverse events (SAE) associated with distant spread of the toxin have yet been reported with its use for dermatologic, blepharospastic or strabismic applications.

 Understand that swallowing and breathing difficulties can be life-threatening.  Be aware that children treated for spasticity are at greatest risk for these symptoms,

but symptoms can also occur in adults treated for spasticity and other conditions.  Understand that side effects may occur within hours of an injection or as late as

several weeks after treatment.

 Understand that the established drug names of the botulinum products have been changed to emphasize the differing dose to potency ratios of these products and the lack of interchangeability among products.

 Be aware that all botulinum toxin products have a Medication Guide and urge patients, their families, and caregivers to review it carefully.

The FDA urges both healthcare professionals and patients to report side effects from the use of botulinum toxin products to the FDA’s MedWatch Adverse Event Reporting program (http://www.fda.gov/Safety/MedWatch/HowToReport).

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Botulism is a neuroparalytic disease caused by neurotoxins produced by the bacteria

Clostridium botulinum. Botulinum neurotoxins (BoNT) are among the most potent

naturally occurring toxins and are a category A biological threat agent. The 7 toxin

serotypes of BoNTs (serotypes A-G) have different toxicities, act through 3 different

intracellular protein targets, and exhibit different durations of effect. Botulism may

follow ingestion of food contaminated with BoNT, from toxin production of C

botulinum present in the intestine or wounds, from inhalation of aerosolized toxin or

by injection.

Intoxication classically presents as an acute, symmetrical, descending flaccid

paralysis. Early diagnosis is important because antitoxin therapy is most effective

when administered early. Confirmatory testing of botulism with BoNT assays or C

botulinum cultures is time-consuming and may be insensitive in the diagnosis of

inhalational botulism. Therefore, the decision to initiate botulinum antitoxin therapy

is primarily based on symptoms and physical examination findings that are consistent

with botulism, with support of epidemiological history and electrophysiological

testing.

Removal of Source of Toxin

Therapy consists of removing the toxin from the gastrointestinal track by inducing

vomiting and bowel movements. If the source of the toxin is in a wound, removal of

the infected tissue surgically is indicated.

Antitoxin

The antitoxin attaches itself to toxin that is circulating in the bloodstream. The

Communicable Disease Ccnter (CDC) has indicated the availability of a heptavalent

botulinum antitoxin (HBAT, Cangene Corporation). HBAT replaces a licensed

bivalent botulinum antitoxin AB and is the only botulinum antitoxin available in the

United States for naturally occurring, noninfant botulism. This botulinum antitoxin is

available only from CDC.

HBAT contains equine-derived antibody to the seven known botulinum toxin types

(A--G). HBAT is composed of <2% intact immunoglobulin G (IgG) and ≥90% Fab

and F(ab')

immunoglobulin fragments. These fragments are created by the enzymatic

cleavage and removal of Fc immunoglobulin components in a process sometimes

referred to as despeciation. Fab and F(ab')

fragments are cleared from circulation

more rapidly than intact IgG (2), and repeat HBAT dosing may be indicated for some

wound or intestinal colonization patients if in situ botulinum toxin production

continues after clearance of antitoxin. In modern clinical practice, antitoxin treatment

has reduced botulism mortality rates from approximately 60% to less than 10%.

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Treatment and Prevention Program. BabyBIG is an orphan drug that consists of

human-derived botulism antitoxin antibodies and is approved by FDA for the

treatment of infant botulism types A and B.

Breathing Assistance

A mechanical ventilator may be necessary when respiratory difficulty occurs. The

ventilator may be required for up to several weeks until the effects of the toxin

gradually lessens. Residual nerve damage may occur and require rehabilitative

therapy to improve speech, swallowing and other functions affected by the disease.

Botulinum toxin is a therapeutic drug which continues to find new clinical

applications. Like all potent pharmaceuticals, it should be employed only by

physicians who have an understanding of its mechanism of action and are prepared to

deal with untoward events following its use. The abuse of botulinum toxin in casual

social settings can result in unanticipated and potentially life threatening

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Figure Legends:

Fig.1 -

Binding

-The heavy chain of onabotulinumtoxinA (BoNTA) neurotoxin binds

to the cell membrane of the motor nerve via a high affinity ―acceptor‖ molecule. This

high-affinity binding action allows for efficient uptake of

BoNTA

neurotoxin by the

motor nerve.

Fig.2 -

Internalizing

- After binding to the cell membrane, the

BoNTA

protein

passes into the motor nerve cytoplasm by endocytosis. The enzymatic

component (light chain) of the

BoNTA

protein is activated in the cytoplasm.

Fig. 3 –

Blocking -

The

BoNTA

light chain, a zinc-dependent metalloprotease,

cleaves the SNAP-25 protein. This prevents the acetylcholine containing vesicles

from attaching to the cell membrane.

Fig. 4 -

Nerve Sprouting -

New nerve endings sprout and connect to the muscle

after the original nerve ending is blocked, renewing the ability of

that nerve to cause muscle contractions.

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18. Erbguth FJ. From poison to remedy: the chequered history of botulinum toxin. J Neural Transm. 2008;115(4):559-65.

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22. Scott A. Development of botulinum toxin. Disability and Rehabilitation. 2007;29(23):1757-1758.

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onabotulinumtoxinA (marketed as Botox/Botox Cosmetic), abobotulinumtoxinA (marketed as Dysport) and rimabotulinumtoxinB (marketed as Myobloc). Available at:

http://www.fda.gov/Drugs/DrugSafety/

PostmarketDrugSafetyInformationforPatientsandProviders/

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36. Leung AK, Keyhani K, Ashenhurst M. Retinal tear and raised intraocular pressure following unintentional intraocular botulinum toxin type A injection. Can J Ophthalmol.

2007;42(5):746-7.

37. Mills RP. Ophthalmic criminology: why did they lose it? Eyenet Magazine. 2010;Feb (2):11. 38. US Food and Drug Administration. Update of safety review of onabotulinumtoxinA

(marketed as Botox/Botox Cosmetic), abobotulinumtoxinA (marketed as Dysport) and rimabotulinumtoxinB (marketed as Myobloc). Available at: http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/

DrugSafetyInformationforHeathcareProfessionals/ucm174959.htm. accessed March 8, 2010.

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Table 1 – FDA-Approved Botulinum Toxin Products and Indications

Trade Name New Drug Name* Old Drug Name

Approved Indications How Supplied

Botox® (Allergan, Inc.)

OnabotulinumtoxinA Botulinum toxin type A

Cervical dystonia, Severe primary axillary hyperhidrosis,

Strabismus, Blepharospasm

100-unit vial*

Botox Cosmetic® (Allergan, Inc.)

OnabotulinumtoxinA Botulinum toxin type A

Temporary improvement in the appearance of moderate-to-severe glabellar lines

100-unit vial*

Dysport® (New Zealand Medical and Scientific Ltd)

AbobotulinumtoxinA Botulinum toxin type A

Cervical dystonia, Temporary improvement in the appearance of moderate-to-severe glabellar lines

300-unit vial*

Myobloc® (Solstice Neurosciences, Inc.)

RimabotulinumtoxinB Botulinum toxin type B

Cervical dystonia 2,500-, 5,000-, and 10,000-unit vials*