Safety considerations in the use of botulinum toxins in children with cerebral palsy (PMR 2010;2:282-284).

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Authors: Sue Apkon, MD and Danielle Cassidy, Pharm.D., BCPS

Authors: Sue Apkon, MD and Danielle Cassidy, Pharm.D., BCPS

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  • 1. Clinical Review: FocusedSafety Considerations in the Use of Botulinum Toxinsin Children With Cerebral PalsySusan D. Apkon, MD, Danielle Cassidy, PharmDThe use of botulinum toxins to decrease spasticity in children with cerebral palsy hasbecome standard of care during the past decade. In 2008 reports of severe adverse events,including death, were reported in children who received injections of these medications.The following discussion focuses on the background of these reports, the response of theU.S. Food and Drug Administration, as well as the safety profile and pharmacokinetics ofbotulinum toxins. Finally, the authors will offer their perspective on the safe use ofbotulinum toxins. PM R 2010;2:282-284INTRODUCTIONThe safe and appropriate use of medications is paramount to the physician code of ethics.Since 2008, physicians caring for children with cerebral palsy (CP) have been challenged byinformation in the lay press regarding the safe and appropriate use of botulinum toxin in thispopulation of patients. In early 2008, reports of children with CP dying after the injectionof botulinum toxin made its way to newspapers and television, prompting physicians andtheir patients to question the safety of this medication [1]. The following discussion focuseson the background of those reports and the response of the U.S. Food and Drug Adminis-tration (FDA). The safety profile and pharmacokinetics of botulinum toxins will be reviewedas well as a summary of the authors’ recommendations on the safe use of botulinum toxins. Anaerobic Clostridium botulinum produces 7 serotypes of neurotoxin, with Botulinumtoxin type A being the most potent and the first to be manufactured for commercial useunder the brand names of Botox (onabotulinumtoxinA; Allergan, Irvine, CA) and Dysport(abobotulinumtoxinA; Ipsen Biopharm Ltd., Wrexham, UK). When injected intramuscu-larly at therapeutic doses, botulinum toxins target receptor binding sites on the motor nerveterminals, and upon internalization, inhibit the release of the neurotransmitter acetylcholineinto the neuromuscular junction. This action causes partial chemical denervation of themuscle and results in a reduction of muscle activity. The pharmacologic affects of botulinumtoxins are temporary, as axonal sprouting and the formation of new neuromuscularjunctions may develop. These affects eventually regress as the function of the originalendplate is re-established over time [2]. The onset of muscle weakness usually occurs within 14 days of treatment and theduration of action averages 3 to 6 months. Because of the eventual reversal of muscledenervation, treatment frequency is usually determined on the basis of individual patientresponse. Dosing intervals of less than 3 months are discouraged because of the risk for S.D.A. Department of Rehabilitation Medicine,development of neutralizing antibodies, which can lead to treatment resistance or decrease University of Washington; and Department of Rehabilitation Medicine, Seattle Children’s,the overall effectiveness of botulinum toxins [3]. M/S W-9847, PO Box 5371, Seattle, WA. The biological activity of the botulinum toxins is measured in units, with 1 unit of Address correspondence to S.D.A.; e-mail:botulinum toxin corresponding to the lethal dose capable of killing 50% of a mouse Susan.apkon@seattlechildrens.org Disclosure: nothing to disclosepopulation (ie, LD50) with the specific activity of Botox being 20 units per nanogram ofbotulinum neurotoxin protein [4]. The units of biological activity between botulinum D.C. Investigational Drug Services & Antico- agulation Clinical Pharmacist, The Children’sproducts are not considered bioequivalent because of distinct manufacturing methods used Hospital, Denver, COfor each formulation. A number of experimental attempts have been made to establish a Disclosure: nothing to disclosedose conversion factor for each botulinum product. However, the conversion factors Submitted for publication December 22,reported in published literature vary, and results from these studies continue to confirm that 2009; accepted February 17, 2010. PM&R © 2010 by the American Academy of Physical Medicine and Rehabilitation 1934-1482/10/$36.00 Vol. 2, 282-284, April 2010282 Printed in U.S.A. DOI: 10.1016/j.pmrj.2010.02.006
  • 2. PM&R Vol. 2, Iss. 4, 2010 283each product differs in terms of unit potencies, efficacy, verse reactions. The petition was a response to reports of hospi-diffusion, duration of action, and side effects. talization and death of 16 people injected with botulinum toxin, In 1989 the FDA approved the use of botulinum toxin A including children with CP who had botulinum toxin injected(Botox) in the treatment of strabismus and blepharospasm. into their lower limbs for control of spasticity.Approval of Botox for cervical dystonia, primary axillary hyper- The FDA embarked on a systematic review of the literature,hidrosis, and glabellar lines was obtained in the subsequent postmarketing Adverse Event Reporting System Database, anddecade. Approval of other botulinum toxin formulations was the clinical studies submitted by the manufacturers of the dif-granted in 2000 (botulinum toxin B; Myobloc) and in 2009 ferent types of botulinum toxins. A search of Adverse Event(botulinum toxin A; Dysport). In March 2010, the FDA granted Reporting System Database revealed 9 deaths in pediatric pa-approval for the use of OnabotulinumtoxinA (Botox) for use in tients younger than 16 years of age, with cause of death listed asadults with upper extremity spasticity due to stroke. Despite cardiorespiratory arrest (n 4), seizure (n 2), fatal arrhyth-the absence of FDA approval in children, use of botulinum mia (n 1), pneumonia (n 1), and stroke (n 1). Dosetoxins is standard practice in the treatment of spasticity in ranges for serious systemic adverse reactions were reported forchildren with CP [5]. Of interest, botulinum toxins have been Botox from 6.25 to 32 units/kg and for Myobloc from 388 toapproved for use in children with CP in Canada, Australia, 625 units/kg. It must be emphasized that all of the children whoand other countries. died reportedly had underlying neuromuscular problems. For Many researchers have reported the efficacy of the botuli- privacy reasons, the complete details about the circumstancesnum toxins over the past decade. Benefits have included a surrounding each of the deaths were not released; however,decrease in spasticity and improvement in range of motion administration of at least one very high dose (32 units/kg) wasand function [6-12]. In 2000, a consensus statement was reported. This dose is well beyond what has been recommendedpublished by 15 experienced clinicians and scientists high- in the pediatric literature.lighting patient selection, dosing guidelines, and injection Additional serious adverse events in pediatric patientstechniques for both upper and lower extremities in children were found in review of the medical literature and includedwith CP [13]. The authors stressed the importance of select- systemic weakness requiring mechanical ventilation and se-ing 1 or 2 muscle groups in the lower limbs and focusing on vere dysphagia requiring gastrostomy feeding [16-22]. Re-treating dynamic tone in the upper limbs. In addition, the use view of adverse events in the adult population identified 225of up to 12 units/kg up to a maximum dose of 300 units was case reports that were highly suggestive of distant spread ofrecommended. To reduce the risk of secondary unrespon- botulinum toxin leading to recognizable signs and symptomssiveness caused by the development of neutralizing antibod- of botulism. Doses in adult patients ranged from 100 to 700ies, the consensus was to inject no more frequently than every units of Botox and 10,000 to 20,000 units of Myobloc.3 months. Additional recommendations focused on the tar- In April 2009 the FDA issued a report on their review of theirgeted dilution, which was a concentration of 100 units in 1 or investigation. The FDA obtained enough evidence that war-2 mL of normal saline. A subsequent review article [14] in ranted a number of changes that would create an impact on thewhich investigators summarized 22 articles published be- prescribing information [23]. The manufacturers of the 3 li-tween 1993 and 2003 reported that the maximum total dose censed botulinum toxins had to strengthen the warnings in theinjected was 400 units with a maximum dose of 29 units/kg, product labeling and include a Boxed Warning highlightingand concentrations varying from 50 to 500 units/mL, with the possibility of distant spread of the toxin, potentiallythe most common being 100 units/mL. Both of these articles causing life-threatening events. They also had to implement adescribed the potential for side effects related to spread of the risk evaluation and mitigation strategy that included a Med-medication to distant sites. Injectors were implored to con- ication Guide to be provided to patients to help them under-sider this spread of medication when selecting the appropri- stand the risks and benefits of the injections, as well as aate dose and concentration to be used. “Dear Health Care Professional” letter emphasizing the risks. In January 2008, the consumer group Public Citizen Finally, the FDA required a change in the names of the 3Health Research Group submitted a petition to the FDA botulinum toxins as a way to highlight the difference inrequesting the agency provide regulatory action regarding potency units of each of the products and remind physiciansthe spread of botulinum toxin from the site that was inten- that they cannot compare or convert doses. The FDA an-tionally injected to a distant site resulting in systemic signs of nounced the new names as OnabotulinumtoxinA (Botox),botulism [15]. This letter requested the FDA send a warning AbobotulinumtoxinA (Dysport), and RimabotulinumtoxinBletter directly to physicians alerting them to the problems (Myobloc.) The FDA also urged physicians to be aware thatassociated with the toxin, including cases of hospitalization children treated for spasticity are at greatest risk for theand death. Additionally, the petition asked the FDA to label systemic symptoms. Toxin spread has occurred at doses usedthe products with a “black box” warning, the strongest warning to treat cervical dystonia, and even at lower doses, swallow-the agency can make, and require physicians to give patients a ing and breathing problems can be life-threatening. In addi-medication guide warning them of possible symptoms of ad- tion, the FDA noted that no serious adverse events caused by
  • 3. 284 Apkon and Cassidy SAFETY AND BOTULINUM TOXINS IN CHILDREN WITH CPdistant spread have been reported with dermatologic use or mittee of the American Academy of Neurology and the Practice Com-for blepharospasm or strabismus at approved doses. Finally, mittee of the Child Neurology Society. Neurology;74:336-343. 6. Ade-Hall RA, Moore AP. Botulinum toxin type A in the treatment ofthe FDA is recommending ongoing monitoring of relevant lower limb spasticity in cerebral palsy. Cochrane Database Syst Revsafety data. 2000:CD001408. 7. Bjornson K, Hays R, Graubert C, et al. Botulinum toxin for spasticity in children with cerebral palsy: A comprehensive evaluation. PediatricsRECOMMENDATIONS 2007;120:49-58. 8. Criswell SR, Crowner BE, Racette BA. The use of botulinum toxinUse of off-label medications such as botulinum toxins in chil- therapy for lower-extremity spasticity in children with cerebral palsy.dren with CP is very common. A recent report identified that Neurosurg Focus 2006;21:e1. 9. Koman LA, Mooney JF 3rd, Smith BP, Walker F, Leon JM. Botulinum toxin62% of pediatric outpatient visits included off-label prescribing type A neuromuscular blockade in the treatment of lower extremity spas-[24]. There was a greater likelihood when a specialist was seeing ticity in cerebral palsy: A randomized, double-blind, placebo-controlledthe child, as is the case frequently in use of botulinum toxin. It is trial. BOTOX Study Group. J Pediatr Orthop 2000;20:108-115.the authors’ recommendation that physicians caring for children 10. Lukban MB, Rosales RL, Dressler D. Effectiveness of botulinum toxin Awith CP heed the safety concerns that have been underscored for upper and lower limb spasticity in children with cerebral palsy: A summary of evidence. J Neural Transm 2009;116:319-331.through the original petition by the Public Citizen Health Re- 11. Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ.search Group and the investigation by the FDA. Physicians must Double-blind study of botulinum A toxin injections into the gastrocnemiusdiscuss with families and patients the potential risk for distant muscle in patients with cerebral palsy. Gait Posture 1999;10:1-9.spread of the toxin and balance this with the benefits that can be 12. Wasiak J, Hoare B, Wallen M. Botulinum toxin A as an adjunct toachieved. Physicians should provide patients and families with treatment in the management of the upper limb in children with spastic cerebral palsy. Cochrane Database Syst Rev 2004:CD003469.the Medication Guide of the neurotoxin being injected. Physi- 13. Graham HK, Aoki KR, Autti-Ramo I, et al. Recommendations for thecians need to be aware that because botulinum toxin is not use of botulinum toxin type A in the management of cerebral palsy. Gaitapproved for treatment of spasticity or children younger than 12 Posture 2000;11:67-79.years of age, there are no approved dosing guidelines. Therefore, 14. Kinnett D. Botulinum toxin A injections in children: Technique andfor safety reasons, the lowest dose necessary should be injected dosing issues. Am J Phys Med Rehabil 2004;83:S59-S64. 15. Public Citizen. Petition to the FDA requesting regulatory action con-and always determined on the basis of the child’s weight. cerning the possible spread of botulinum toxin (Botox, Myobloc) from The use of botulinum toxins in the treatment of children with the site of injection to other parts of the body (HRG Publication #1834).CP does decrease spasticity and improve range of motion. De- 2008. Available at: http://www.citizen.org/publications/release.cfm?spite the concern for distant spread, when used cautiously ID 7559. Accessed February 23, 2010.botulinum toxins should be considered a generally safe and 16. Albavera-Hernandez C, Rodriguez JM, Idrovo AJ. Safety of botulinum toxin type A among children with spasticity secondary to cerebralappropriate treatment for localized upper and lower limb spas- palsy: a systematic review of randomized clinical trials. Clin Rehabilticity. Specific goals need to be identified before injecting botu- 2009;23:394-407.linum toxins and close follow-up completed after the injections 17. Crowner BE, Racette BA. Prospective study examining remote effects ofto insure that results are realized. This step allows for any botulinum toxin a in children with cerebral palsy. Pediatr Neurolpotential risk to be off-set by benefits to the child. Finally, it is 2008;39:253-258. 18. Willis AW, Crowner B, Brunstrom JE, Kissel A, Racette BA. High doseimperative for those injecting these neurotoxins to participate in botulinum toxin A for the treatment of lower extremity hypertonicity inquality research to better understand safety and long-term effi- children with cerebral palsy. Dev Med Child Neurol 2007;49:818-822.cacy in children with CP. 19. Crowner BE, Brunstrom JE, Racette BA. Iatrogenic botulism due to therapeutic botulinum toxin a injection in a pediatric patient. Clin Neuropharmacol 2007;30:310-313.REFERENCES 20. Howell K, Selber P, Graham HK, Reddihough D. Botulinum neurotoxin A: An unusual systemic effect. J Paediatr Child Health 2007;43:499-501. 1. Early Communication about an Ongoing Safety Review of Botox and Botox 21. Partikian A, Mitchell WG. Iatrogenic botulism in a child with spastic Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinum toxin Type quadriparesis. J Child Neurol 2007;22:1235-1237. B). 2008. Accessed at http://www.fda.gov/Drugs/DrugSafety/Postmarket 22. 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