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afety Considerations in the Use of Botulinum Toxinsn Children With Cerebral Palsy

usan D. Apkon, MD, Danielle Cassidy, PharmD

SURMASD

DaHD

he use of botulinum toxins to decrease spasticity in children with cerebral palsy hasecome standard of care during the past decade. In 2008 reports of severe adverse events,

ncluding death, were reported in children who received injections of these medications.he following discussion focuses on the background of these reports, the response of the.S. Food and Drug Administration, as well as the safety profile and pharmacokinetics ofotulinum toxins. Finally, the authors will offer their perspective on the safe use ofotulinum toxins.

PM R 2010;2:282-284

NTRODUCTION

he safe and appropriate use of medications is paramount to the physician code of ethics.ince 2008, physicians caring for children with cerebral palsy (CP) have been challenged bynformation in the lay press regarding the safe and appropriate use of botulinum toxin in thisopulation of patients. In early 2008, reports of children with CP dying after the injectionf botulinum toxin made its way to newspapers and television, prompting physicians andheir patients to question the safety of this medication [1]. The following discussion focusesn the background of those reports and the response of the U.S. Food and Drug Adminis-ration (FDA). The safety profile and pharmacokinetics of botulinum toxins will be revieweds well as a summary of the authors’ recommendations on the safe use of botulinum toxins.

Anaerobic Clostridium botulinum produces 7 serotypes of neurotoxin, with Botulinumoxin type A being the most potent and the first to be manufactured for commercial usender the brand names of Botox (onabotulinumtoxinA; Allergan, Irvine, CA) and DysportabobotulinumtoxinA; Ipsen Biopharm Ltd., Wrexham, UK). When injected intramuscu-arly at therapeutic doses, botulinum toxins target receptor binding sites on the motor nerveerminals, and upon internalization, inhibit the release of the neurotransmitter acetylcholinento the neuromuscular junction. This action causes partial chemical denervation of the

uscle and results in a reduction of muscle activity. The pharmacologic affects of botulinumoxins are temporary, as axonal sprouting and the formation of new neuromuscularunctions may develop. These affects eventually regress as the function of the originalndplate is re-established over time [2].

The onset of muscle weakness usually occurs within 14 days of treatment and theuration of action averages 3 to 6 months. Because of the eventual reversal of muscleenervation, treatment frequency is usually determined on the basis of individual patientesponse. Dosing intervals of less than 3 months are discouraged because of the risk forevelopment of neutralizing antibodies, which can lead to treatment resistance or decreasehe overall effectiveness of botulinum toxins [3].

The biological activity of the botulinum toxins is measured in units, with 1 unit ofotulinum toxin corresponding to the lethal dose capable of killing 50% of a mouseopulation (ie, LD50) with the specific activity of Botox being 20 units per nanogram ofotulinum neurotoxin protein [4]. The units of biological activity between botulinumroducts are not considered bioequivalent because of distinct manufacturing methods usedor each formulation. A number of experimental attempts have been made to establish aose conversion factor for each botulinum product. However, the conversion factors

eported in published literature vary, and results from these studies continue to confirm that

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PM&R © 2010 by the American Academy of P1934-1482/10/$36.00

Printed in U.S.A.82

.D.A. Department of Rehabilitation Medicine,niversity of Washington; and Department ofehabilitation Medicine, Seattle Children’s,/S W-9847, PO Box 5371, Seattle, WA.ddress correspondence to S.D.A.; e-mail:usan.apkon@seattlechildrens.orgisclosure: nothing to disclose

.C. Investigational Drug Services & Antico-gulation Clinical Pharmacist, The Children’sospital, Denver, COisclosure: nothing to disclose

ubmitted for publication December 22,009; accepted February 17, 2010.

hysical Medicine and RehabilitationVol. 2, 282-284, April 2010

DOI: 10.1016/j.pmrj.2010.02.006

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283PM&R Vol. 2, Iss. 4, 2010

ach product differs in terms of unit potencies, efficacy,iffusion, duration of action, and side effects.

In 1989 the FDA approved the use of botulinum toxin ABotox) in the treatment of strabismus and blepharospasm.pproval of Botox for cervical dystonia, primary axillary hyper-idrosis, and glabellar lines was obtained in the subsequentecade. Approval of other botulinum toxin formulations wasranted in 2000 (botulinum toxin B; Myobloc) and in 2009botulinum toxin A; Dysport). In March 2010, the FDA grantedpproval for the use of OnabotulinumtoxinA (Botox) for use indults with upper extremity spasticity due to stroke. Despitehe absence of FDA approval in children, use of botulinumoxins is standard practice in the treatment of spasticity inhildren with CP [5]. Of interest, botulinum toxins have beenpproved for use in children with CP in Canada, Australia,nd other countries.

Many researchers have reported the efficacy of the botuli-um toxins over the past decade. Benefits have included aecrease in spasticity and improvement in range of motionnd function [6-12]. In 2000, a consensus statement wasublished by 15 experienced clinicians and scientists high-

ighting patient selection, dosing guidelines, and injectionechniques for both upper and lower extremities in childrenith CP [13]. The authors stressed the importance of select-

ng 1 or 2 muscle groups in the lower limbs and focusing onreating dynamic tone in the upper limbs. In addition, the usef up to 12 units/kg up to a maximum dose of 300 units wasecommended. To reduce the risk of secondary unrespon-iveness caused by the development of neutralizing antibod-es, the consensus was to inject no more frequently than every

months. Additional recommendations focused on the tar-eted dilution, which was a concentration of 100 units in 1 ormL of normal saline. A subsequent review article [14] inhich investigators summarized 22 articles published be-

ween 1993 and 2003 reported that the maximum total dosenjected was 400 units with a maximum dose of 29 units/kg,nd concentrations varying from 50 to 500 units/mL, withhe most common being 100 units/mL. Both of these articlesescribed the potential for side effects related to spread of theedication to distant sites. Injectors were implored to con-

ider this spread of medication when selecting the appropri-te dose and concentration to be used.

In January 2008, the consumer group Public Citizenealth Research Group submitted a petition to the FDA

equesting the agency provide regulatory action regardinghe spread of botulinum toxin from the site that was inten-ionally injected to a distant site resulting in systemic signs ofotulism [15]. This letter requested the FDA send a warning

etter directly to physicians alerting them to the problemsssociated with the toxin, including cases of hospitalizationnd death. Additionally, the petition asked the FDA to labelhe products with a “black box” warning, the strongest warninghe agency can make, and require physicians to give patients a

edication guide warning them of possible symptoms of ad- t

erse reactions. The petition was a response to reports of hospi-alization and death of 16 people injected with botulinum toxin,ncluding children with CP who had botulinum toxin injectednto their lower limbs for control of spasticity.

The FDA embarked on a systematic review of the literature,ostmarketing Adverse Event Reporting System Database, andhe clinical studies submitted by the manufacturers of the dif-erent types of botulinum toxins. A search of Adverse Eventeporting System Database revealed 9 deaths in pediatric pa-

ients younger than 16 years of age, with cause of death listed asardiorespiratory arrest (n � 4), seizure (n � 2), fatal arrhyth-ia (n � 1), pneumonia (n � 1), and stroke (n � 1). Dose

anges for serious systemic adverse reactions were reported forotox from 6.25 to 32 units/kg and for Myobloc from 388 to25 units/kg. It must be emphasized that all of the children whoied reportedly had underlying neuromuscular problems. Forrivacy reasons, the complete details about the circumstancesurrounding each of the deaths were not released; however,dministration of at least one very high dose (32 units/kg) waseported. This dose is well beyond what has been recommendedn the pediatric literature.

Additional serious adverse events in pediatric patientsere found in review of the medical literature and included

ystemic weakness requiring mechanical ventilation and se-ere dysphagia requiring gastrostomy feeding [16-22]. Re-iew of adverse events in the adult population identified 225ase reports that were highly suggestive of distant spread ofotulinum toxin leading to recognizable signs and symptomsf botulism. Doses in adult patients ranged from 100 to 700nits of Botox and 10,000 to 20,000 units of Myobloc.

In April 2009 the FDA issued a report on their review of theirnvestigation. The FDA obtained enough evidence that war-anted a number of changes that would create an impact on therescribing information [23]. The manufacturers of the 3 li-ensed botulinum toxins had to strengthen the warnings in theroduct labeling and include a Boxed Warning highlightinghe possibility of distant spread of the toxin, potentiallyausing life-threatening events. They also had to implement aisk evaluation and mitigation strategy that included a Med-cation Guide to be provided to patients to help them under-tand the risks and benefits of the injections, as well as aDear Health Care Professional” letter emphasizing the risks.inally, the FDA required a change in the names of the 3otulinum toxins as a way to highlight the difference inotency units of each of the products and remind physicianshat they cannot compare or convert doses. The FDA an-ounced the new names as OnabotulinumtoxinA (Botox),bobotulinumtoxinA (Dysport), and RimabotulinumtoxinB

Myobloc.) The FDA also urged physicians to be aware thathildren treated for spasticity are at greatest risk for theystemic symptoms. Toxin spread has occurred at doses usedo treat cervical dystonia, and even at lower doses, swallow-ng and breathing problems can be life-threatening. In addi-

ion, the FDA noted that no serious adverse events caused by

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284 Apkon and Cassidy SAFETY AND BOTULINUM TOXINS IN CHILDREN WITH CP

istant spread have been reported with dermatologic use oror blepharospasm or strabismus at approved doses. Finally,he FDA is recommending ongoing monitoring of relevantafety data.

ECOMMENDATIONS

se of off-label medications such as botulinum toxins in chil-ren with CP is very common. A recent report identified that2% of pediatric outpatient visits included off-label prescribing24]. There was a greater likelihood when a specialist was seeinghe child, as is the case frequently in use of botulinum toxin. It ishe authors’ recommendation that physicians caring for childrenith CP heed the safety concerns that have been underscored

hrough the original petition by the Public Citizen Health Re-earch Group and the investigation by the FDA. Physicians mustiscuss with families and patients the potential risk for distantpread of the toxin and balance this with the benefits that can bechieved. Physicians should provide patients and families withhe Medication Guide of the neurotoxin being injected. Physi-ians need to be aware that because botulinum toxin is notpproved for treatment of spasticity or children younger than 12ears of age, there are no approved dosing guidelines. Therefore,or safety reasons, the lowest dose necessary should be injectednd always determined on the basis of the child’s weight.

The use of botulinum toxins in the treatment of children withP does decrease spasticity and improve range of motion. De-

pite the concern for distant spread, when used cautiouslyotulinum toxins should be considered a generally safe andppropriate treatment for localized upper and lower limb spas-icity. Specific goals need to be identified before injecting botu-inum toxins and close follow-up completed after the injectionso insure that results are realized. This step allows for anyotential risk to be off-set by benefits to the child. Finally, it is

mperative for those injecting these neurotoxins to participate inuality research to better understand safety and long-term effi-acy in children with CP.

EFERENCES1. Early Communication about an Ongoing Safety Review of Botox and Botox

Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinum toxin TypeB). 2008. Accessed at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070366.htm. Accessed February 23, 2010.

2. Dolly JO. Therapeutic and research exploitation of botulinum neuro-toxins. Eur J Neurol 1997;4:S5-S10.

3. Yablon SA, Brashear A, Gordon MF, et al. Formation of neutralizingantibodies in patients receiving botulinum toxin type A for treatment ofpoststroke spasticity: A pooled-data analysis of three clinical trials. ClinTher 2007;29:683-690.

4. Product Information: BOTOX (onobotulinumtoxinA). Irvine, CA: Al-lergan Pharmaceuticals; 2009.

5. Delgado MR, Hirtz D, Aisen M, et al. Practice parameter: Pharmacologictreatment of spasticity in children and adolescents with cerebral palsy

(an evidence-based review): Report of the Quality Standards Subcom-

mittee of the American Academy of Neurology and the Practice Com-mittee of the Child Neurology Society. Neurology;74:336-343.

6. Ade-Hall RA, Moore AP. Botulinum toxin type A in the treatment oflower limb spasticity in cerebral palsy. Cochrane Database Syst Rev2000:CD001408.

7. Bjornson K, Hays R, Graubert C, et al. Botulinum toxin for spasticity inchildren with cerebral palsy: A comprehensive evaluation. Pediatrics2007;120:49-58.

8. Criswell SR, Crowner BE, Racette BA. The use of botulinum toxintherapy for lower-extremity spasticity in children with cerebral palsy.Neurosurg Focus 2006;21:e1.

9. Koman LA, Mooney JF 3rd, Smith BP, Walker F, Leon JM. Botulinum toxintype A neuromuscular blockade in the treatment of lower extremity spas-ticity in cerebral palsy: A randomized, double-blind, placebo-controlledtrial. BOTOX Study Group. J Pediatr Orthop 2000;20:108-115.

0. Lukban MB, Rosales RL, Dressler D. Effectiveness of botulinum toxin Afor upper and lower limb spasticity in children with cerebral palsy: Asummary of evidence. J Neural Transm 2009;116:319-331.

1. Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ.Double-blind study of botulinum A toxin injections into the gastrocnemiusmuscle in patients with cerebral palsy. Gait Posture 1999;10:1-9.

2. Wasiak J, Hoare B, Wallen M. Botulinum toxin A as an adjunct totreatment in the management of the upper limb in children with spasticcerebral palsy. Cochrane Database Syst Rev 2004:CD003469.

3. Graham HK, Aoki KR, Autti-Ramo I, et al. Recommendations for theuse of botulinum toxin type A in the management of cerebral palsy. GaitPosture 2000;11:67-79.

4. Kinnett D. Botulinum toxin A injections in children: Technique anddosing issues. Am J Phys Med Rehabil 2004;83:S59-S64.

5. Public Citizen. Petition to the FDA requesting regulatory action con-cerning the possible spread of botulinum toxin (Botox, Myobloc) fromthe site of injection to other parts of the body (HRG Publication #1834).2008. Available at: http://www.citizen.org/publications/release.cfm?ID�7559. Accessed February 23, 2010.

6. Albavera-Hernandez C, Rodriguez JM, Idrovo AJ. Safety of botulinumtoxin type A among children with spasticity secondary to cerebralpalsy: a systematic review of randomized clinical trials. Clin Rehabil2009;23:394-407.

7. Crowner BE, Racette BA. Prospective study examining remote effects ofbotulinum toxin a in children with cerebral palsy. Pediatr Neurol2008;39:253-258.

8. Willis AW, Crowner B, Brunstrom JE, Kissel A, Racette BA. High dosebotulinum toxin A for the treatment of lower extremity hypertonicity inchildren with cerebral palsy. Dev Med Child Neurol 2007;49:818-822.

9. Crowner BE, Brunstrom JE, Racette BA. Iatrogenic botulism due totherapeutic botulinum toxin a injection in a pediatric patient. ClinNeuropharmacol 2007;30:310-313.

0. Howell K, Selber P, Graham HK, Reddihough D. Botulinum neurotoxin A:An unusual systemic effect. J Paediatr Child Health 2007;43:499-501.

1. Partikian A, Mitchell WG. Iatrogenic botulism in a child with spasticquadriparesis. J Child Neurol 2007;22:1235-1237.

2. Kolaski K, Ajizian SJ, Passmore L, Pasutharnchat N, Koman LA, SmithBP. Safety profile of multilevel chemical denervation procedures usingphenol or botulinum toxin or both in a pediatric population. Am J PhysMed Rehabil 2008;87:556-566.

3. Food and Drug Administration. Follow-up to the February 8, 2008,Early Communication about an Ongoing Safety Review of Botox andBotox Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinumtoxin Type B). FDA response to petition, 2009. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm143819.htm.

4. Bazzano AT, Mangione-Smith R, Schonlau M, Suttorp MJ, Brook RH.Off-label prescribing to children in the United States outpatient setting.

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