The pooled incidences of treatment-emergent adverse events (TEAEs) were examined by indication using the integrated clinical database of Merz-sponsored, placebo-controlled, or repeat-dose studies of incobotulinumtoxinA in adults with cervical dystonia, blepharospasm, limb spasticity, sialorrhea, or essential tremor of the upper limb. Overall incidences of TEAEs, serious TEAEs, TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (TEAESIs; indicating possible toxin spread), and treatment-related (TR) events were determined for incobotulinumtoxinA and placebo after a single injection and for repeated dose cycles of incobotulinumtoxinA. The most frequent events after a single dose of incobotulinumtoxinA are summarized. After a single cycle, incidences of overall TEAEs were similar between incobotulinumtoxinA and the placebo in most indications, although between-indication differences were observed. Few TEAEs led to incobotulinumtoxinA discontinuation; there were no fatal TEAEs with incobotulinumtoxinA. In general, repeated cycles did not increase the incidence of any event. The most frequent TR-TEAEs were indication-dependent, including dysphagia for indications affecting the head or neck. The TR-TEAESIs across all indications were most commonly muscular weakness, dysphagia and dry mouth. Overall, the results of this pooled analysis support and extend the favorable safety and tolerability profile of incobotulinumtoxinA for the treatment of adult neurological disorders established by individual clinical studies.

Faculty of Medicine and Dentistry and University Hospital Palacký University Olomouc 779 00 Olomouc Czech Republic

Kansas City Bone and Joint Clinic Overland Park KS 66211 USA

Merz Pharmaceuticals LLC Raleigh NC 27615 USA

Merz Therapeutics GmbH 60318 Frankfurt am Main Germany

Parkinson Klinik Ortenau 77709 Wolfach Germany

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Merz Pharmaceuticals GmbH, Xeomin Prescribing Information. [(accessed on 8 August 2022)];2019 May; Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125360s074lbl.pdf.

Merz Pharma UK Ltd Xeomin 200 Units Powder for Solution for Injection. Oct 4, 2021. [(accessed on 8 August 2022)]. Available online: https://www.medicines.org.uk/emc/product/2162/smpc.

Comella C.L., Jankovic J., Truong D.D., Hanschmann A., Grafe S.U.S. XEOMIN Cervical Dystonia Study Group. Efficacy and safety of incobotulinumtoxinA (NT 201, XEOMIN®, botulinum neurotoxin type A, without accessory proteins) in patients with cervical dystonia. J. Neurol. Sci. 2011;308:103–109. doi: 10.1016/j.jns.2011.05.041. PubMed DOI

Comella C., Hauser R.A., Isaacson S.H., Truong D., Oguh O., Hui J., Molho E.S., Brodsky M., Furr-Stimming E., Comes G., et al. Efficacy and safety of two incobotulinumtoxinA injection intervals in cervical dystonia patients with inadequate benefit from standard injection intervals of botulinum toxin: Phase 4, open-label, randomized, noninferiority study. Clin. Park Relat. Disord. 2022;6:100142. doi: 10.1016/j.prdoa.2022.100142. PubMed DOI PMC

Evidente V.G., Fernandez H.H., LeDoux M.S., Brashear A., Grafe S., Hanschmann A., Comella C.L. A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin(®)) in cervical dystonia. J. Neural. Transm. 2013;120:1699–1707. doi: 10.1007/s00702-013-1048-3. PubMed DOI PMC

Dressler D., Paus S., Seitzinger A., Gebhardt B., Kupsch A. Long-term efficacy and safety of incobotulinumtoxin A injections in patients with cervical dystonia. J. Neurol. Neurosurg. Psychiatry. 2013;84:1014–1019. doi: 10.1136/jnnp-2012-303608. PubMed DOI PMC

Jankovic J., Comella C., Hanschmann A., Grafe S. Efficacy and safety of incobotulinumtoxinA (NT 201, Xeomin) in the treatment of blepharospasm-a randomized trial. Mov. Disord. 2011;26:1521–1528. doi: 10.1002/mds.23658. PubMed DOI

Truong D.D., Gollomp S.M., Jankovic J., LeWitt P.A., Marx M., Hanschmann A., Fernandez H.H. Xeomin US Blepharospasm Study Group. Sustained efficacy and safety of repeated incobotulinumtoxinA (Xeomin(®)) injections in blepharospasm. J. Neural. Transm. 2013;120:1345–1353. doi: 10.1007/s00702-013-0998-9. PubMed DOI PMC

Mitsikostas D.D., Dekundy A., Sternberg K., Althaus M., Pagan F. IncobotulinumtoxinA for the treatment of blepharospasm in toxin-naïve subjects: A multi-center, double-blind, randomized, placebo-controlled trial. Adv Ther. 2020;37:4249–4265. doi: 10.1007/s12325-020-01427-6. PubMed DOI

Barnes M., Schnitzler A., Medeiros L., Aguilar M., Lehnert-Batar A., Minnasch P. Efficacy and safety of NT 201 for upper limb spasticity of various etiologies--a randomized parallel-group study. Acta Neurol. Scand. 2010;122:295–302. doi: 10.1111/j.1600-0404.2010.01354.x. PubMed DOI

Kaňovský P., Slawek J., Denes Z., Platz T., Sassin I., Comes G., Grafe S. Efficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticity. Clin. Neuropharmacol. 2009;32:259–265. doi: 10.1097/WNF.0b013e3181b13308. PubMed DOI

Kaňovský P., Slawek J., Denes Z., Platz T., Comes G., Grafe S., Pulte I. Efficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticity. J. Rehabil. Med. 2011;43:486–492. doi: 10.2340/16501977-0796. PubMed DOI

Elovic E.P., Munin M.C., Kaňovský P., Hanschmann A., Hiersemenzel R., Marciniak C. Randomized, placebo-controlled trial of incobotulinumtoxina for upper-limb post-stroke spasticity. Muscle Nerve. 2016;53:415–421. doi: 10.1002/mus.24776. PubMed DOI PMC

Marciniak C., Munin M.C., Brashear A., Rubin B.S., Patel A.T., Slawek J., Hanschmann A., Hiersemenzel R., Elovic E.P. IncobotulinumtoxinA efficacy and safety in adults with upper-limb spasticity following stroke: Results from the open-label extension period of a phase 3 study. Adv. Ther. 2019;36:187–199. doi: 10.1007/s12325-018-0833-7. PubMed DOI PMC

Masakado Y., Abo M., Kondo K., Saeki S., Saitoh E., Dekundy A., Hanschmann A., Kaji R. J-PURE Study Group. Efficacy and safety of incobotulinumtoxinA in post-stroke upper-limb spasticity in Japanese subjects: Results from a randomized, double-blind, placebo-controlled study (J-PURE) J. Neurol. 2020;267:2029–2041. doi: 10.1007/s00415-020-09777-5. PubMed DOI PMC

Jost W.H., Friedman A., Michel O., Oehlwein C., Slawek J., Bogucki A., Ochudlo S., Banach M., Pagan F., Flatau-Baqué B., et al. SIAXI: Placebo-controlled, randomized, double-blind study of incobotulinumtoxinA for sialorrhea. Neurology. 2019;92:e1982–e1991. doi: 10.1212/WNL.0000000000007368. PubMed DOI PMC

Jost W.H., Friedman A., Michel O., Oehlwein C., Slawek J., Bogucki A., Ochudlo S., Banach M., Pagan F., Flatau-Baqué B., et al. Long-term incobotulinumtoxinA treatment for chronic sialorrhea: Efficacy and safety over 64 weeks. Parkinsonism. Relat. Disord. 2020;70:23–30. doi: 10.1016/j.parkreldis.2019.11.024. PubMed DOI

Benecke R., Jost W.H., Kanovsky P., Ruzicka E., Comes G., Grafe S. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology. 2005;64:1949–1951. doi: 10.1212/01.WNL.0000163767.99354.C3. PubMed DOI

Jankovic J., Kenney C., Grafe S., Goertelmeyer R., Comes G. Relationship between various clinical outcome assessments in patients with blepharospasm. Mov Disord. 2009;24:407–413. doi: 10.1002/mds.22368. PubMed DOI

Wissel J., Bensmail D., Ferreira J.J., Molteni F., Satkunam L., Moraleda S., Rekand T., McGuire J., Scheschonka A., Flatau-Baqué B., et al. TOWER study investigators. Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity: The TOWER study. Neurology. 2017;88:1321–1328. doi: 10.1212/WNL.0000000000003789. PubMed DOI PMC

Masakado Y., Kagaya H., Kondo K., Otaka Y., Dekundy A., Hanschmann A., Geister T.L., Kaji R. Efficacy and safety of IncobotulinumtoxinA in the treatment of lower limb spasticity in Japanese subjects. Front. Neurol. 2022;13:832937. doi: 10.3389/fneur.2022.832937. PubMed DOI PMC

Jog M., Lee J., Scheschonka A., Chen R., Ismail F., Boulias C., Hobson D., King D., Althaus M., Simon O., et al. Tolerability and efficacy of customized incobotulinumtoxinA injections for essential tremor: A randomized, double-blind, placebo-controlled study. Toxins. 2020;12:807. doi: 10.3390/toxins12120807. PubMed DOI PMC

Coleman W.P., 3rd, Sattler G., Weissenberger P., Hast M.A., Hanschmann A. Safety of incobotulinumtoxinA in the treatment of facial lines: Results from a pooled analysis of randomized, prospective, controlled clinical studies. Dermatol. Surg. 2017;43((Suppl. S3)):S293–S303. doi: 10.1097/DSS.0000000000001409. PubMed DOI

Bach K., Simman R. The Multispecialty Toxin: A literature review of botulinum toxin. Plast Reconstr. Surg. Glob. Open. 2022;10:e4228. doi: 10.1097/GOX.0000000000004228. PubMed DOI PMC

Duarte G.S., Rodrigues F.B., Marques R.E., Castelão M., Ferreira J., Sampaio C., Moore A.P., Costa J. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst. Rev. 2020;11:CD004900. PubMed PMC

Ruiz-Roca J.A., Pons-Fuster E., Lopez-Jornet P. Effectiveness of the botulinum toxin for treating sialorrhea in patients with Parkinson’s disease: A systematic review. J. Clin. Med. 2019;8:317. doi: 10.3390/jcm8030317. PubMed DOI PMC

Yu Y.C., Chung C.C., Tu Y.K., Hong C.T., Chen K.H., Tam K.W., Kuan Y.C. Efficacy and safety of botulinum toxin for treating sialorrhea: A systematic review and meta-analysis. Eur. J. Neurol. 2022;29:69–80. doi: 10.1111/ene.15083. PubMed DOI

Orsini M., Leite M.A., Chung T.M., Bocca W., de Souza J.A., de Souza O.G., Moreira R.P., Bastos V.H., Teixeira S., Oliveira A.B., et al. Botulinum Neurotoxin Type A in Neurology: Update. Neurol. Int. 2015;7:5886. doi: 10.4081/ni.2015.5886. PubMed DOI PMC

Petracca M., Guidubaldi A., Ricciardi L., Ialongo T., Del Grande A., Mulas D., Di Stasio E., Bentivoglio A.R. Botulinum Toxin A and B in sialorrhea: Long-term data and literature overview. Toxicon. 2015;107:129–140. doi: 10.1016/j.toxicon.2015.08.014. PubMed DOI

Stokholm M.G., Bisgård C., Vilholm O.J. Safety and administration of treatment with botulinum neurotoxin for sialorrhoea in ALS patients: Review of the literature and a proposal for tailored treatment. Amyotroph Lateral Scler Front. Degener. 2013;14:516–520. doi: 10.3109/21678421.2013.830312. PubMed DOI

Naumann M., Dressler D., Hallett M., Jankovic J., Schiavo G., Segal K.R., Truong D. Evidence-based review and assessment of botulinum neurotoxin for the treatment of secretory disorders. Toxicon. 2013;67:141–152. doi: 10.1016/j.toxicon.2012.10.020. PubMed DOI

Walshe M., Smith M., Pennington L. Interventions for drooling in children with cerebral palsy. Cochrane Database Syst. Rev. 2012;11:CD008624. doi: 10.1002/14651858.CD008624.pub3. PubMed DOI PMC

Rodwell K., Edwards P., Ware R.S., Boyd R. Salivary gland botulinum toxin injections for drooling in children with cerebral palsy and neurodevelopmental disability: A systematic review. Dev. Med. Child Neurol. 2012;54:977–987. doi: 10.1111/j.1469-8749.2012.04370.x. PubMed DOI

Rodrigues F.B., Duarte G.S., Castelão M., Marques R.E., Ferreira J., Sampaio C., Moore A.P., Costa J. Botulinum toxin type A versus anticholinergics for cervical dystonia. Cochrane Database Syst Rev. 2021;4:CD004312. doi: 10.1002/14651858.CD004312.pub3. PubMed DOI PMC

Marsili L., Bologna M., Jankovic J., Colosimo C. Long-term efficacy and safety of botulinum toxin treatment for cervical dystonia: A critical reappraisal. Expert Opin. Drug Saf. 2021;20:695–705. doi: 10.1080/14740338.2021.1915282. PubMed DOI

Wissel J. Towards flexible and tailored botulinum neurotoxin dosing regimens for focal dystonia and spasticity–Insights from recent studies. Toxicon. 2018;147:100–106. doi: 10.1016/j.toxicon.2018.01.018. PubMed DOI

Duarte G.S., Castelão M., Rodrigues F.B., Marques R.E., Ferreira J., Sampaio C., Moore A.P., Costa J. Botulinum toxin type A versus botulinum toxin type B for cervical dystonia. Cochrane Database Syst. Rev. 2016;10:CD004314. doi: 10.1002/14651858.CD004314.pub3. PubMed DOI PMC

Han Y., Stevens A.L., Dashtipour K., Hauser R.A., Mari Z. A mixed treatment comparison to compare the efficacy and safety of botulinum toxin treatments for cervical dystonia. J. Neurol. 2016;263:772–780. doi: 10.1007/s00415-016-8050-2. PubMed DOI PMC

Mills R.R., Pagan F.L. Patient considerations in the treatment of cervical dystonia: Focus on botulinum toxin type A. Patient Prefer. Adherence. 2015;9:725–731. doi: 10.2147/PPA.S75459. PubMed DOI PMC

Bonikowski M., Sławek J. Safety and efficacy of Botulinum toxin type A preparations in cerebral palsy—An evidence-based review. Neurol. Neurochir. Pol. 2021;55:158–164. doi: 10.5603/PJNNS.a2021.0032. PubMed DOI

Intiso D., Simone V., Bartolo M., Santamato A., Ranieri M., Gatta M.T., Di Rienzo F. High dosage of botulinum toxin type A in adult subjects with spasticity following acquired central nervous system damage: Where are we at? Toxins. 2020;12:315. doi: 10.3390/toxins12050315. PubMed DOI PMC

Santamato A., Micello M.F., Ranieri M., Valeno G., Albano A., Baricich A., Cisari C., Intiso D., Pilotto A., Logroscino G., et al. Employment of higher doses of botulinum toxin type A to reduce spasticity after stroke. J. Neurol. Sci. 2015;350:1–6. doi: 10.1016/j.jns.2015.01.033. PubMed DOI

Esquenazi A., Albanese A., Chancellor M.B., Elovic E., Segal K.R., Simpson D.M., Smith C.P., Ward A.B. Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon. 2013;67:115–128. doi: 10.1016/j.toxicon.2012.11.025. PubMed DOI

Novak I., Campbell L., Boyce M., Fung V.S., Cerebral Palsy Institute Botulinum toxin assessment, intervention and aftercare for cervical dystonia and other causes of hypertonia of the neck: International consensus statement. Eur. J. Neurol. 2010;17:94–108. doi: 10.1111/j.1468-1331.2010.03130.x. PubMed DOI

Elia A.E., Filippini G., Calandrella D., Albanese A. Botulinum neurotoxins for post-stroke spasticity in adults: A systematic review. Mov. Disord. 2009;24:801–812. doi: 10.1002/mds.22452. PubMed DOI

Schulte-Mattler W.J. Use of botulinum toxin A in adult neurological disorders: Efficacy, tolerability and safety. CNS Drugs. 2008;22:725–738. doi: 10.2165/00023210-200822090-00002. PubMed DOI

Sheean G. Botulinum toxin treatment of adult spasticity: A benefit-risk assessment. Drug Saf. 2006;29:31–48. doi: 10.2165/00002018-200629010-00003. PubMed DOI

Hallett M., Albanese A., Dressler D., Segal K.R., Simpson D.M., Truong D., Jankovic J. Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders. Toxicon. 2013;67:94–114. doi: 10.1016/j.toxicon.2012.12.004. PubMed DOI

Naumann M., Albanese A., Heinen F., Molenaers G., Relja M. Safety and efficacy of botulinum toxin type A following long-term use. Eur. J. Neurol. 2006;13:35–40. doi: 10.1111/j.1468-1331.2006.01652.x. PubMed DOI

Charles P.D. Botulinum neurotoxin serotype A: A clinical update on non-cosmetic uses. Am. J. Health Syst. Pharm. 2004;61:S11–S23. doi: 10.1093/ajhp/61.suppl_6.S11. PubMed DOI

Rodrigues F.B., Duarte G.S., Marques R.E., Castelão M., Ferreira J., Sampaio C., Moore A.P., Costa J. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database Syst. Rev. 2020;11:CD003633. PubMed PMC

Rosales R.L., Chua-Yap A.S. Evidence-based systematic review on the efficacy and safety of botulinum toxin-A therapy in post-stroke spasticity. J. Neural. Transm. 2008;115:617–623. doi: 10.1007/s00702-007-0869-3. PubMed DOI

Santamato A., Cinone N., Panza F., Letizia S., Santoro L., Lozupone M., Daniele A., Picelli A., Baricich A., Intiso D., et al. Botulinum toxin type A for the treatment of lower limb spasticity after stroke. Drugs. 2019;79:143–160. doi: 10.1007/s40265-018-1042-z. PubMed DOI

Pirazzini M., Rossetto O., Eleopra R., Montecucco C. Botulinum neurotoxins: Biology, pharmacology, and toxicology. Pharmacol. Rev. 2017;69:200–235. doi: 10.1124/pr.116.012658. PubMed DOI PMC

Berweck S., Banach M., Gaebler-Spira D., Chambers H.G., Schroeder A.S., Geister T.L., Althaus M., Hanschmann A., Vacchelli M., Bonfert M.V., et al. Safety profile and lack of immunogenicity of incobotulinumtoxinA in pediatric spasticity and sialorrhea: A pooled analysis. Toxins. 2022;14:585. doi: 10.3390/toxins14090585. PubMed DOI PMC

Hefter H., Rosenthal D., Jansen A., Brauns R., Ürer B., Bigalke H., Hartung H.P., Meuth S.G., Lee J.I., Albrecht P., et al. Significantly lower antigenicity of incobotulinumtoxin than abo- or onabotulinumtoxin. J. Neurol. 2022;270:788–796. doi: 10.1007/s00415-022-11395-2. PubMed DOI PMC

Naumann M., Boo L.M., Ackerman A.H., Gallagher C.J. Immunogenicity of botulinum toxins. J. Neural Transm. 2013;120:275–290. doi: 10.1007/s00702-012-0893-9. PubMed DOI PMC

Fabbri M., Leodori G., Fernandes R.M., Bhidayasiri R., Marti M.J., Colosimo C., Ferreira J.J. neutralizing antibody and botulinum toxin therapy: A systematic review and meta-analysis. Neurotox Res. 2016;29:105–117. doi: 10.1007/s12640-015-9565-5. PubMed DOI

Rahman E., Alhitmi H.K., Mosahebi A. Immunogenicity to botulinum toxin type A: A systematic review with meta-analysis across therapeutic indications. Aesthet. Surg. J. 2022;42:106–120. doi: 10.1093/asj/sjab058. PubMed DOI

Walter U., Mühlenhoff C., Benecke R., Dressler D., Mix E., Alt J., Wittstock M., Dudesek A., Storch A., Kamm C. Frequency and risk factors of antibody-induced secondary failure of botulinum neurotoxin therapy. Neurology. 2020;94:e2109–e2120. doi: 10.1212/WNL.0000000000009444. PubMed DOI

Carr W.W., Jain N., Sublett J.W. Immunogenicity of botulinum toxin formulations: Potential therapeutic implications. Adv. Ther. 2021;38:5046–5064. doi: 10.1007/s12325-021-01882-9. PubMed DOI PMC

Albrecht P., Jansen A., Lee J.I., Moll M., Ringelstein M., Rosenthal D., Bigalke H., Aktas O., Hartung H.P., Hefter H. High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology. 2019;92:e48–e54. doi: 10.1212/WNL.0000000000006688. PubMed DOI

Bellows S., Jankovic J. Immunogenicity associated with botulinum toxin treatment. Toxins. 2019;11:491. doi: 10.3390/toxins11090491. PubMed DOI PMC

Hefter H., Samadzadeh S. Botulinum Toxin—Recent Topics and Applications. IntechOpen; London, UK: 2022. Clinical relevance of neutralizing antibodies in botulinum neurotoxin type A. DOI

Brin M.F., Comella C.L., Jankovic J., Lai F., Naumann M., CD-017 BoNTA Study Group Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov. Disord. 2008;23:1353–1360. doi: 10.1002/mds.22157. PubMed DOI