{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:56:26Z","timestamp":1793073386644,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T00:00:00Z","timestamp":1728950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Revance Therapeutics, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>The first-line management of cervical dystonia (CD) symptoms is intramuscular injection of botulinum toxin type A (BoNTA). However, a comparison of safety among BoNTAs is difficult because, per regulatory authorities, units of BoNTA activity are not interchangeable. Dysphagia and muscle weakness are widely considered two key adverse events to monitor closely in the treatment of CD. This integrated analysis compared the safety of BoNTAs approved for CD in the US by evaluating relationships between the incidence of dysphagia and muscle weakness in prescribing information and the core neurotoxin content. Coefficients The coefficients of determination (R2) and trendlines were estimated via regression-based lines of best fit. Adverse drug reaction (ADR) rates were strongly correlated with core neurotoxin amounts for conventional BoNTAs (slope coefficients: dysphagia = 0.048, R2 = 0.74; muscle weakness = 0.096, R2 = 0.82). The published ADR rates at approved doses for conventional BoNTAs were higher compared with DaxibotulinumtoxinA (DAXI; DAXXIFY\u00ae, Revance Therapeutics, Inc., Nashville, TN, USA) by core neurotoxin content. The use of a core neurotoxin amount was found to be an effective method for comparing the safety of BoNTA products. Current clinical trials suggest that DAXI, a novel BoNTA formulation, provides a potentially wider safety margin compared with other approved BoNTAs for CD. The lower amount of core neurotoxin administered at approved doses compared with conventional BoNTAs may explain low on-target ADRs like muscle weakness, whereas reduced diffusion from the injection site is thought to be responsible for low off-target ADRs like dysphagia.<\/jats:p>","DOI":"10.3390\/toxins16100442","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T07:28:35Z","timestamp":1729495715000},"page":"442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dysphagia and Muscle Weakness Secondary to Botulinum Toxin Type A Treatment of Cervical Dystonia: A Drug Class Analysis of Prescribing Information"],"prefix":"10.3390","volume":"16","author":[{"given":"Khashayar","family":"Dashtipour","sequence":"first","affiliation":[{"name":"Department of Neurology\/Movement Disorders, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6508-2640","authenticated-orcid":false,"given":"Han S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Permanente Medical Group, Greater Southern Alameda Area\u2014San Leandro\/Fremont, San Leandro, CA 94577, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Ellenbogen","sequence":"additional","affiliation":[{"name":"Quest Research Institute, Farmington Hills, MI 48334, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3223-2597","authenticated-orcid":false,"given":"Rashid","family":"Kazerooni","sequence":"additional","affiliation":[{"name":"Revance Therapeutics, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5482-5313","authenticated-orcid":false,"given":"Todd M.","family":"Gross","sequence":"additional","affiliation":[{"name":"Revance Therapeutics, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Hollander","sequence":"additional","affiliation":[{"name":"Revance Therapeutics, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5488-6594","authenticated-orcid":false,"given":"Conor J.","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Revance Therapeutics, Nashville, TN 37203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41572-018-0023-6","article-title":"Dystonia","volume":"4","author":"Balint","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1136\/jnnp-2020-325193","article-title":"Quality of Life in Isolated Dystonia: Non-Motor Manifestations Matter","volume":"92","author":"Junker","year":"2021","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1007\/s00415-020-10378-5","article-title":"Head Tremor and Pain in Cervical Dystonia","volume":"268","author":"Vu","year":"2021","journal-title":"J. Neurol."},{"key":"ref_4","first-page":"CD003633","article-title":"Botulinum Toxin Type A Therapy for Cervical Dystonia","volume":"11","author":"Rodrigues","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1212\/WNL.0000000000002560","article-title":"Practice Guideline Update Summary: Botulinum Neurotoxin for the Treatment of Blepharospasm, Cervical Dystonia, Adult Spasticity, and Headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology","volume":"86","author":"Simpson","year":"2016","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Spiegel, L.L., Ostrem, J.L., and Bledsoe, I.O. (2020). FDA Approvals and Consensus Guidelines for Botulinum Toxins in the Treatment of Dystonia. Toxins, 12.","DOI":"10.3390\/toxins12050332"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1002\/mds.25582","article-title":"Diffusion, Spread, and Migration of Botulinum Toxin","volume":"28","author":"Jankovic","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1124\/pr.116.012658","article-title":"Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology","volume":"69","author":"Pirazzini","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10655","DOI":"10.3389\/dyst.2022.10655","article-title":"Botulinum Toxin in the Treatment of Cervical Dystonia: Evidence-Based Review","volume":"1","author":"Hammoud","year":"2022","journal-title":"Dystonia"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Contarino, M.F., Van Den Dool, J., Balash, Y., Bhatia, K., Giladi, N., Koelman, J.H., Lokkegaard, A., Marti, M.J., Postma, M., and Relja, M. (2017). Clinical Practice: Evidence-Based Recommendations for the Treatment of Cervical Dystonia With Botulinum Toxin. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00035"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/nrd3801","article-title":"The Determination and Interpretation of the Therapeutic Index in Drug Development","volume":"11","author":"Muller","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1468-1331.2006.01649.x","article-title":"Using Translational Medicine to Understand Clinical Differences Between Botulinum Toxin Formulations","volume":"13","author":"Aoki","year":"2006","journal-title":"Eur. J. Neurol."},{"key":"ref_13","unstructured":"Allergan (2024, March 26). BOTOX (Onabotulinumtoxin A) for Injection, for Intramuscular, Intradetrusor, or Intradermal Use Prescribing Information. Available online: https:\/\/media.allergan.com\/actavis\/actavis\/media\/allergan-pdf-documents\/product-prescribing\/20190620-BOTOX-100-and-200-Units-v3-0USPI1145-v2-0MG1145.pdf."},{"key":"ref_14","unstructured":"Ipsen (2024, March 26). DYSPORT (AbobotulinumtoxinA) for Injection, for Intramuscular Use Prescribing Information. Available online: https:\/\/www.ipsen.com\/websites\/Ipsen_Online\/wp-content\/uploads\/sites\/9\/2019\/01\/21084019\/Dysport_Full_Prescribing_Information.pdf."},{"key":"ref_15","unstructured":"Merz (2024, March 26). XEOMIN (IncobotulinumtoxinA) for Injection, for Intramuscular or Intraglandular Use Prescribing Information. Available online: https:\/\/www.xeominaesthetic.com\/wp-content\/uploads\/2019\/05\/XEOMIN-Full-Prescribing-Information-including-MedGuide.pdf."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wei, X., Li, L., Wu, Y., and Liu, J. (2022). Cell-Penetrating Botulinum Neurotoxin Type A with Improved Cellular Uptake and Therapeutic Index. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.828427"},{"key":"ref_17","unstructured":"Revance (2024, March 26). DAXXIFY\u00ae (daxibotulinumtoxinA-Lanm) for Injection, for Intramuscular Use, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2023\/761127s002lbl.pdf."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1080\/17425247.2023.2251399","article-title":"A Technology Evaluation of the Atypical Use of a CPP-Containing Peptide in the Formulation and Performance of a Clinical Botulinum Toxin Product","volume":"20","author":"Dowdy","year":"2023","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_19","first-page":"S113","article-title":"Novel Peptide Excipient RTP004 Enhances the Binding of Botulinum Neurotoxin Type A Cell Binding Domain HC to Rat Brain Synaptosomes","volume":"156","author":"Weisemann","year":"2018","journal-title":"Toxicon"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.toxicon.2021.11.101","article-title":"A Cell-Penetrating Peptide Binds Directly to and Enhances Membrane Binding of the Core Toxin of Botulinum Toxin Type A (BoNTA)","volume":"214","author":"Fang","year":"2022","journal-title":"Toxicon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107364","DOI":"10.1016\/j.toxicon.2024.107364","article-title":"A Cell Penetrating Peptide Enhances Membrane Binding of Botulinum Neurotoxin Type A and Increases SNAP-25 Cleavage","volume":"237","author":"Batista","year":"2024","journal-title":"Toxicon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e208091","DOI":"10.1212\/WNL.0000000000208091","article-title":"Efficacy and Safety of DaxibotulinumtoxinA for Injection (DAXI) in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial","volume":"102","author":"Comella","year":"2024","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1365-2710.2007.00835.x","article-title":"Comparing Two Botulinum Toxin Type A Formulations Using Manufacturers\u2019 Product Summaries","volume":"32","author":"Wenzel","year":"2007","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"593","DOI":"10.4103\/0019-5154.193662","article-title":"Biostatistics Series Module 6: Correlation and Linear Regression","volume":"61","author":"Hazra","year":"2016","journal-title":"Indian J. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1213\/ANE.0000000000002864","article-title":"Correlation Coefficients: Appropriate Use and Interpretation","volume":"126","author":"Schober","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/hed.2880120504","article-title":"Botulinum A Toxin for the Treatment of Spasmodic Torticollis: Dysphagia and Regional Toxin Spread","volume":"12","author":"Borodic","year":"1990","journal-title":"Head Neck"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1177\/0269215511412799","article-title":"Safety and Self-Reported Efficacy of Botulinum Toxin for Adult Spasticity in Current Clinical Practice: A Prospective Observational Study","volume":"26","author":"Muller","year":"2012","journal-title":"Clin. Rehabil."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.toxicon.2011.05.012","article-title":"Characterization of Diffusion and Duration of Action of a New Botulinum Toxin Type A Formulation","volume":"58","author":"Stone","year":"2011","journal-title":"Toxicon"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1007\/s40265-021-01631-w","article-title":"Overview of DaxibotulinumtoxinA for Injection: A Novel Formulation of Botulinum Toxin Type A","volume":"81","author":"Solish","year":"2021","journal-title":"Drugs"},{"key":"ref_30","unstructured":"Lee, H., Batista, A., and Gallagher, C. (2024, January 13\u201318). Influence of Novel Formulation in DaxibotulinumtoxinA on Efficacy for Treatment of Cervical Dystonia. Proceedings of the AAN Annual Meeting, Denver, CO, USA."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.toxicon.2012.10.020","article-title":"Evidence-Based Review and Assessment of Botulinum Neurotoxin for the Treatment of Secretory Disorders","volume":"67","author":"Naumann","year":"2013","journal-title":"Toxicon"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1126\/science.1123654","article-title":"SV2 is the Protein Receptor for Botulinum Neurotoxin A","volume":"312","author":"Dong","year":"2006","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Winner, B.M., Bodt, S.M.L., and McNutt, P.M. (2020). Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228715"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gallagher, C.J., Bowsher, R.R., Clancy, A., Dover, J.S., Humphrey, S., Liu, Y., and Prawdzik, G. (2023). Clinical Immunogenicity of DaxibotulinumtoxinA for Injection in Glabellar Lines: Pooled Data from the SAKURA Phase 3 Trials. Toxins, 15.","DOI":"10.3390\/toxins15010060"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Field, M., Splevins, A., Picaut, P., van der Schans, M., Langenberg, J., Noort, D., Snyder, D., and Foster, K. (2018). AbobotulinumtoxinA (Dysport\u00ae), OnabotulinumtoxinA (Botox\u00ae), and IncobotulinumtoxinA (Xeomin\u00ae) Neurotoxin Content and Potential Implications for Duration of Response in Patients. Toxins, 10.","DOI":"10.3390\/toxins10120535"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jns.2011.05.041","article-title":"Efficacy and Safety of IncobotulinumtoxinA (NT 201, XEOMIN\u00ae, Botulinum Neurotoxin Type A, Without Accessory Proteins) in Patients With Cervical Dystonia","volume":"308","author":"Comella","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1136\/jnnp.64.1.13","article-title":"What Is the Optimal Dose of Botulinum Toxin A in the Treatment of Cervical Dystonia? Results of a Double Blind, Placebo Controlled, Dose Ranging Study Using Dysport. German Dystonia Study Group","volume":"64","author":"Poewe","year":"1998","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1080\/00207454.2017.1406935","article-title":"A 500 U\/2 mL Dilution of AbobotulinumtoxinA vs. Placebo: Randomized Study in Cervical Dystonia","volume":"128","author":"Lew","year":"2018","journal-title":"Int. J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.parkreldis.2010.03.002","article-title":"Long-Term Efficacy and Safety of Botulinum Toxin Type A (Dysport) in Cervical Dystonia","volume":"16","author":"Truong","year":"2010","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/mds.20403","article-title":"Efficacy and Safety of Botulinum Type A Toxin (Dysport) in Cervical Dystonia: Results of the First US Randomized, Double-Blind, Placebo-Controlled Study","volume":"20","author":"Truong","year":"2005","journal-title":"Mov. Disord."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1007\/s004150170028","article-title":"Efficacy and Safety of a Standardised 500 Unit Dose of Dysport (Clostridium Botulinum Toxin Type A Haemaglutinin Complex) in a Heterogeneous Cervical Dystonia Population: Results of a Prospective, Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel Group Study","volume":"248","author":"Wissel","year":"2001","journal-title":"J. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1212\/01.wnl.0000183055.81056.5c","article-title":"Comparison of Botulinum Toxin Serotypes A and B for the Treatment of Cervical Dystonia","volume":"65","author":"Comella","year":"2005","journal-title":"Neurology"},{"key":"ref_43","unstructured":"Allergan (2024, May 24). SPLA 9 l-01 84 Response to CR Letter, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2000\/botaller122100r2p5.pdf."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/10\/442\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:13:26Z","timestamp":1760112806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/10\/442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,15]]},"references-count":43,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["toxins16100442"],"URL":"https:\/\/doi.org\/10.3390\/toxins16100442","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,15]]}}}