Safety and Efficacy of Multiuse Botulinum Toxin Vials for Intralaryngeal Injection

Transcription

1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Safety and Efficacy of Multiuse Botulinum Toxin Vials for Intralaryngeal Injection Emily M. Barrow, MD; Clark A. Rosen, MD; Edie R. Hapner, PhD, CCC-SLP; Sarah Smith, PharmD; Jeanne L. Hatcher, MD; Blake Simpson, MD; Michael M. Johns III, MD Objectives/Hypothesis: Centers for Disease Control and Prevention guidelines maintain that single-use vials cannot be used for multiple patients. Botox product labeling states that the reconstituted toxin should be used within 4 hours on a single patient based on concerns of reduced potency, contamination, and consequent infections. The purpose of this study was to determine the safety and efficacy of using single-use vials in a multidose fashion. Study Design: Prospective study and cohort chart review. Methods: A multi-institutional three-part study was performed between May 2013 and October 2013: 1) a summation of subjects recall of their past experiences (symptoms/response) with previous multidose Botox injections, 2) a prospective study of intralaryngeal injections, and 3) a chart review of injection responses in a subset of the cohort. Results: Seven hundred forty-three subjects receiving 6,216 injections demonstrated zero infection-related complications on retrospective chart review. One hundred seventy-nine subjects recalled 24.0% overall adverse events, 10.6% redness, 7.3% pain and swelling at the injection site, and 0% fever. One hundred seventy-four subjects prospectively reported 12.6% overall adverse events. The self-reported efficacy rate of Botox injection was 96.6%. Conclusions: The low rates of adverse events following the use of Botox in a multipatient fashion are consistent with other percutaneous injections. No evidence of infection was found with multidose Botox use. Given the low incidence of side effects and high success rate, Botox can be used both safely and effectively in a multipatient fashion. Key Words: Botox, botulinum toxin, larynx, voice, safety, efficacy, multidose. Level of Evidence: 4 Laryngoscope, 125: , 2015 From the Department of Otolaryngology Head and Neck Surgery (E.M.B., E.R.H., M.M.J.), Emory University School of Medicine, Atlanta, Georgia; Department of Otolaryngology Head and Neck Surgery (C.A.R., S.S.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Otolaryngology Head and Neck Surgery (J.L.H., B.S.), University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A. Editor s Note: This Manuscript was accepted for publication November 7, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Michael M. Johns III, MD, Emory Voice Center, 550 Peachtree Street, Suite , Atlanta, GA michael.johns2@emory.edu DOI: /lary INTRODUCTION Botulinum toxin is a natural neurotoxin produced by the Clostridium botulinum bacteria. Exposure to this toxin results in muscular weakness through inhibition of acetylcholine release at the neuromuscular junction. Botulinum toxin type A (Btx A) is widely distributed as Botox (Allergan, Irvine, CA). Btx A is used to treat dystonia, spasticity, tremors, and voice disorders. 1 BtxAis useful in treating vocal manifestations of neurolaryngeal disease, mainly spasmodic dysphonia. Btx A is widely accepted for treatment of spasmodic dysphonia, and is recognized as the primary therapy by the American Academy of Otolaryngology Head and Neck Surgery. 2,3 Botox is manufactured by Allergan (Irvine, CA) as a vacuum-dried concentrated powder in 100-U vials. Allergan recommends reconstituting each vacuum-dried vial of Botox with sterile, nonpreserved 0.9% sodium chloride. 4 Botox product labeling states that the reconstituted toxin should be refrigerated at 2 Cto8 C (36 F 46 F) and used within 4 hours on a single patient (single-use vial) based on concerns of reduced potency, contamination, and consequent infections. 4,5 A single-use vial of medication is labeled as such by the manufacturer and is intended for administration in a single patient for a single procedure. The Centers for Disease Control and Prevention s (CDC) guidelines maintain that all medications labeled as single dose or single use be used for only one patient. Compliance with these guidelines is required for Joint Commission Accreditation. 6 Such practices are in place to protect patients from infections resulting from contaminated medications due to unsafe use. 6 Between 1998 and 2009, 51 outbreaks of the hepatitis B and hepatitis C virus, as well as 21 bacterial outbreaks, were reported due to unsafe injection practices, adding support to the CDC s policy. 7,8 However, these documented instances of contamination by the CDC were related to reinsertion of used needles into multiple-dose vials, and the use of a single needle/syringe to dispense medications to multiple patients. 5 These unsafe injection practices can cause contamination and infection regardless of whether vials are labeled for single or multiple patient use. Botox is available in 50, 100, or 200-U vials, and a substantial quantity of the product is discarded when used on one patient. This is especially evident in laryngology 1149

2 given that typical intralaryngeal Btx A injections use between and 5 U total. If a single Botox vial is used for each individual, these patients are required to pay for large quantities of a costly product that they will not be utilizing. Furthermore, the product may not be saved for later use in the patient due to concerns about decreased Botox efficacy after 4 hours. If physicians choose to utilize single-use Botox vials in multiple patients, they may delay patient treatment until they can consolidate those requiring injections into a single clinic to preserve the efficacy of the product and utilize Botox within the designated 4-hour time period. However, this can often inconvenience patients by limiting or restricting them to certain time periods and intervals for treatment. Despite the CDC s and manufacturer s guidelines, physicians often use single-use Btx A vials on multiple patients and store the product for longer than the recommended 4 hours for later use. A survey of 1,000 physician members of the American Society for Dermatologic Surgery assessed the use of Btx A including length of storage after reconstitution, single versus multiple patient use, viewpoints on product safety when stored beyond manufacturers recommendations, and instances of local infection. 5 Of these physicians, 98.7% used Btx A vials on multiple patients, 68.6% kept reconstituted Btx A vials stored at 4 C for 1 week or more, and 67% believed reconstituted vials could be safely kept for patient treatment for 1 to 4 weeks. 5 There were no instances of local infections ever documented by this group despite using the vials on multiple patients. 5 Multiple studies have examined the safety and efficacy of Btx A use in multiple patients and storage beyond the suggested 4 hours. Initial animal and in vitro studies demonstrated decreases in duration of action and potency, respectively, under these conditions. 9,10 Despite these findings, clinical evaluations with human beings have not shown reduced duration of action or potency after the use of Btx A reconstituted and stored for various time intervals including 1 week, 2 weeks, 6 weeks, and 6 months Furthermore, none of these studies reported any instances of infection after using reconstituted Botox that was stored at 4 C for longer than the recommended 4 hours Further studies demonstrated no evidence of bacterial contamination of reconstituted single-use Btx A vials used in multiple patients and stored for periods of up to 10 months. 9,17 19 Thomas and Siupsinskiene examined the efficacy of reconstituted Btx A for laryngeal dystonia, but no study has examined the safety of using single-use Btx A vials in multiple patients with laryngeal disorders. 2 If Btx A from single-use vials can be safely injected in multiple patients, large quantities of a costly product can be preserved, and healthcare costs can be substantially reduced. This study aimed to analyze both the safety and efficacy of using reconstituted Btx A from single-use vials for multiple patients for intralaryngeal muscle injections. MATERIALS AND METHODS Institutional review board (IRB) approval was obtained for each study site individually, with a data collection IRB from 1150 Emory University. Between May 2013 and October 2013, a three-part study was carried out at the Emory Voice Center (EVC), University of Pittsburgh Voice Center (UPVC), and University of Texas Health Science Center (UTHSCSA) voice center as detailed below. Botulinum Btx A injections Btx A injections given during this study were performed using a percutaneous, electromyography-guided injection via a transcricothyroid membrane approach according to the routine practice at each institution. 20 Subjects undergoing Btx A injections for vocal disorders are scheduled during the same clinic (typically a 5-hour time span). Prior to clinic, Btx A injection was prepared using the following method: sanitizing the top of the vials with an alcohol wipe and using a new 18-gauge needle. Next, 0.9% normal saline was placed into 100-U Btx A vials for reconstitution. Directly after reconstitution, predetermined amounts of Btx A are drawn up for subject use, using a new needle to puncture the vial with separate syringes for each subject. The needle is discarded after the Btx A is drawn up. The remaining reconstituted Btx A that is not used during the clinic time is refrigerated at 4 C for use the following week. Study Part 1: Recall of Patient Experiences (Symptoms/Response) With Previous Intralaryngeal Btx A Injections Analysis of subjects recall of their previous experience (symptoms/response) with intralaryngeal Btx A injections for vocal disorders was performed at the three clinical sites. Between July 2013 and October 2013, established patients completed a questionnaire at the time of their injection (Fig. 1). The questionnaire assessed adverse events including infectionrelated signs, symptoms, and complications that may have been experienced with previous Btx A injections (pain, redness, or swelling at the injection site as well as a history of fever immediately following a previous Btx A injection). Subjects were also asked about any previous episodes of failed injections (no effect) from a previous Btx A injection. A retrospective chart review for each participant was performed to assess the total number of injections previously received. Study Part 2: Prospective Study of Subjects Experiences With Their Most Recent Btx A Injection A prospective analysis of subjects experiences with their most recent Btx A injection was performed at all three sites. All subjects underwent intralaryngeal Btx A injections and were called 1 week postprocedure per routine clinic protocol to report information on infection-related adverse events (pain, redness and swelling around the injection site, fever). Study Part 3: Retrospective Study of Previous Btx A Injection Experiences A retrospective chart review of previous subject injection experiences from January 2003 to May 2013 was performed at the EVC. The total number of Btx A injections each received during this time period was determined. At the EVC, all patients were contacted by phone 7 days following Btx A injection, and any adverse events were documented in the medical record. Medical records were reviewed, looking for problems following a Btx A injection. This review focused on complaints such as fever, and redness, swelling, or pain at the injection site.

3 subjects and total number of previous injections. A two-tailed Pearson product-moment correlation test with an a 5.05 was used to assess the correlation between the number of previous injections and adverse events as well as the number of failed (no effect) injections. An analysis of variation with an a 5.05 was used to compare the incidence of adverse events among all institutions. To compare the incidence of adverse events among individual institutions, we used a two-tailed t test with an a 5.05 done with Microsoft Excel (Microsoft Corp., Richmond, WA). RESULTS Fig. 1. Past Botox experience questionnaire. Statistics Descriptive statistics were used to evaluate the incidence of adverse infection-related events among the total number of Part 1: Prospective Study of Subjects Recall of Their Cumulative Experiences (Symptoms/ Response) With Previous Btx A Injections One hundred seventy-nine subjects were seen for scheduled intralaryngeal Btx A injections at the EVC (66 subjects), UPVC (78 subjects), and UTHSCSA (35 subjects) (Table I). All completed a questionnaire regarding infection-related adverse events following previous Btx A injections for vocal disorders and success of previous Btx A injections. The 179 subjects recruited for this study had undergone 3,423 injections in total. The 66 subjects at EVC had 1,088 previous injections in total, with an average of At UPVC, 78 subjects underwent 1,758 previous injections in total with an average of The 35 subjects at UTHSCSA had 577 previous Btx A injections with an average of injections. A total of 43 subjects at all institutions (24.02%, which represent 5.81% of all the injections) recalled at least one adverse event (pain, redness, swelling, or fever) after previous Btx A injections. Forty-two percent TABLE I. Incidence and Rate of Adverse Events Occurring After Previous Botox Injections in Total Number of Patients and Total Number of Cumulative Injections. EVC, n patients 5 66, n injections 5 1,088 UPVC, n patients 5 78, n injections 5 1,758 UTHSCSA, n patients 5 35, n injections All Institutions, n patients 5 179, n injections 5 3,423 Redness, n (%) Patients 0 (0%) 15 (19.24%) 4 (11.43%) 19 (10.6%) Injections 0 (0%) 61 (3.47%) 33 (5.72%) 94 (2.75%) Pain, n (%) Patients 0 (0%) 9 (11.54%) 4 (11.43%) 13 (7.26%) Injections 0 (0%) 55 (3.13%) 23 (3.99%) 78 (2.28%) Swelling, n (%) Patients 0 (0%) 9 (11.54%) 4 (11.43%) 13 (7.26%) Injections 0 (0%) 21 (1.19%) 6 (1.04%) 27 (0.79%) Fever, n (%) Patients 0 (0%) 0 (0%) 0 (0%) 0 (0%) Injections 0 (0%) 0 (0%) 0 (0%) 0 (0%) All adverse events, n (%) Patients 0 (0%) 33 (42.31%) 10 (28.57%) 43 (24.02%) Injections 0 (0%) 137 (7.79%) 62 (10.75%) 199 (5.81%) Treatment failure, no effect, n (%) Patients 19 (28.79%) 20 (25.64%) 11 (31.43%) 50 (27.93%) Injections 48 (4.41%) 45 (2.56%) 22 (3.81%) 115 (3.36%) EVC 5 Emory Voice Center; UPVC 5 University of Pittsburgh Voice Center; UTHSCSA 5 University of Texas Health Science Center. 1151

4 TABLE II. Incidence of Adverse Events Occurring After Most Recent Botox Injection in Total Number of Patients. EVC, n patients 5 65 UPVC, n patients 5 81 UTHSCSA, n patients 5 28 All Institutions, n patients Redness, n (%) 0 (0%) 4 (4.94%) 5 (17.86%) 9 (5.17%) Pain, n (%) 0 (0%) 5 (6.17%) 3 (10.71%) 8 (4.60%) Swelling, n (%) 0 (0%) 2 (2.47%) 2 (7.14%) 4 (2.30%) Fever, n (%) 0 (0%) 1 (1.23%) 0 (0%) 1 (0.57%) All adverse events, n (%) 0 (0%) 12 (14.81%) 10 (35.71%) 22 (12.64%) EVC 5 Emory Voice Center; UPVC 5 University of Pittsburgh Voice Center; UTHSCSA 5 University of Texas Health Science Center. of subjects (7.79% of injections) at UPVC and 28.57% of subjects (10.75% of injections) at UTHSCSA had experienced at least one of these events. No subjects (0%) at Emory University experienced any adverse events. Nineteen of 179 subjects (10.61%, 2.75% of injections) recalled redness at the site of the Btx A injection lasting more than 2 hours. Nineteen percent of subjects (3.47% of injections) seen at UPVC, and 11.43% of subjects (5.72% of injections) seen at UTHSCA had experienced redness. No subjects (0%) at EVC experienced any redness lasting more than 2 hours after previous Btx A injections. Thirteen of the 179 (7.26%) subjects participating in this study (2.28% of injections) recalled pain at the site of the Btx A injection. Eleven percent of the subjects seen at UPVC (3.13% of injections) and 11.43% of subjects seen at UTHSCSA (3.99% of injections) had experienced pain post-btx A injection. No subjects (0%) experienced pain at EVC. The incidence of swelling was similar to that of pain post-btx A injection. Seven percent of the 179 subjects recalled swelling at injection site, with incidences of 11.5%t and 11.43% at UPVC and UTHSCSA, respectively. No subjects (0%) experienced swelling at the site of injection at EVC. These rates differed when comparing the total number of injections (3432) to those resulting in swelling at the injection site (27), with an overall incidence of 0.79%. Of the 179 subjects participating in this study, none had previously experienced fever after receiving Btx A injections for vocal disorders. Twenty-eight percent of subjects experienced a failed injection (no effect) with previous Btx A therapy (EVC 29.79%, UPVC 25.64%, UTHSCSA 31.43%). However, only 3.36% of the total injections at all institutions resulted in failure (EVC 4.41%, UPVC 2.56%, UTHSCSA 3.81%). There was no significant difference in the incidence of failed injections among all institutions (P 5.23) or when comparing individual institutions. Part 2: Prospective Study of Subjects Experiences With Their Most Recent Btx A Injection One hundred seventy-nine subjects underwent Btx A injections for vocal disorders at the EVC, UPVC, and UTHSCSA. Of these 179 subjects, 174 participated in the prospective study analyzing their experiences with their most recent Btx A injection (Table II) Of the 174 subjects participating in this portion of the study, 22 (12.64%) experienced pain, redness, swelling, or fever after previous Btx A injections. In total, nine of the 174 (5.17%) experienced redness after their most recent Btx A injection. Eight of the 174 subjects (4.6%) experienced pain after their Btx A injection. Four of the 174 subjects (2.3%) had swelling at the injection site after their most recent Btx A treatment. Only one of the 174 subjects (0.57%) experienced fever after their most recent injection. Part 3: Retrospective Study of Previous Btx A Injections Seven hundred forty-three subjects underwent Btx A injections at EVC. These subjects underwent a total of 6,216 injections during this time period, with an average of injections per subject (range, 1 48 injections). During a retrospective chart review, no infectionrelated adverse events were found to have occurred. Furthermore, no subject was seen in the clinic or admitted for fever or signs/symptoms of infection. DISCUSSION This study was designed in an effort to demonstrate that Btx A is both safe and effective in treating neurologic vocal disorders when used as a multidose vial. In 1986, Blitzer et al. demonstrated the efficacy of Btx A injections in spasmodic dysphonia. 21 Concerns regarding the efficacy of reconstituted Btx A stored beyond the recommended 4 hours have largely been challenged by studies demonstrating that Btx A stored for 1 week, 2 weeks, 6 weeks, and 6 months maintains both potency and duration of action This study demonstrates similar findings through a review of a large cohort of patients experiences with previous Btx A injections. In all three institutions participating in this study, injection failure (no effect) was identified in 3.36% of injections, which amounts to 96.64% efficacy, despite the use of reconstituted Btx A beyond the recommended time. These findings are consistent with the results of Thomas and Siupsinskiene. 2 A survey of 1,000 physician members of the American Society for Dermatologic Surgery found that 98.7% used single-use Btx A vials on multiple patients, and stored the product for longer than the recommended 4 hours without a documented instance of local infection. 5 Results from the retrospective chart review of subjects

5 undergoing Btx A injections at the EVC between January 2003 and May 2013 support this finding (part 3). During this time period, Btx A from single-use vials were injected in multiple subjects. In our chart review, there was no indication of any infection-related complications or adverse events. Results from this study demonstrate that Btx A from a single-use vial injected into multiple patients does not result in infection-related events if proper injection safety techniques are performed. In this study, 24.02% of subjects recalled adverse events occurring after previous Btx A injections, yet these events only occurred after 5.81% of injections. There was no correlation between the number of previous injections and incidence of previous events. Although subjects recalled redness at the injection site with previous Btx A treatment more than all other adverse events, this accounted for <3% of all injections and was not correlated with the total number of previous injections. Pain and swelling were also noted after previous Btx A injections; however, pain occurred more often than swelling. Fever was also not a significant component of postinjection complications, with only 1 subject reporting fever after their most recent injection. Although these data demonstrate that subjects can experience local cutaneous reactions to Btx A injections, we believe they are related to the act of percutaneous needle placement and not related to the use of the vial in a multidose fashion. In this study, there was a significant difference in the incidence of adverse events reported after previous Botox injections (P ) and those after patients most recent injection (P ) among all institutions. The reason for this differing incidence is likely due to the slight differences in survey administration at each institution. At Emory University, questionnaires regarding adverse events after previous injections were given to patients during their scheduled Botox appointments. A member of the study team specifically explained the questionnaire to each patient, emphasizing that the questions were inquiring about infectionrelated adverse events and complications. No patient felt they had ever experienced an infection from their Botox injection. Many patients questioned the study team about the specific items within the questionnaire. Questions regarding redness and swelling were described to the study team member as bruising or minor trauma from the injection process itself. This redness occurred immediately after the injection, never worsened, and improved within several hours of the injection. No patients felt that this was attributed to any sort of infectious process. Furthermore, questions regarding pain at the injection site were described as pain during the actual injection and some throat discomfort after the injection. This likely explains the differences in reported adverse events. Btx A is known to cause generalized reactions including nausea, fatigue, malaise, flu-like symptoms, and rashes. 22 Furthermore, sequelae of percutaneous Btx A injections include pain, edema, erythema, ecchymosis, and headache. 22 It is therefore difficult to assess whether the adverse events reported in this study are due to infection or merely the result of the injection itself. In 2009, Brin et al. published a meta-analysis comparing adverse events in subjects receiving Btx A and placebo injections for the treatment of glabellar and crow s lateral canthal lines. 23 They examined the incidence of injection-site pain (1.7% vs. 1.4%), edema (1.4 vs. 0.3%), and erythema (0.7% vs. 0.2%), yet found no significant difference in adverse events between Btx A and placebo injections. This indicates that these events are likely due to the injection process and unrelated to the actual medication. A similar study by Cote et al. reported skin/injection site reactions in up to 35.4% of subjects receiving Btx A injections. 24 Specifically, 10% of subjects reported injection site edema, 13.7% injection site pain, and 2.6% bruising. As indicated by these previous studies, it is likely that the adverse events reported by subjects in this study are due to the effects of percutaneous injection rather than infection related to the use of a multidose vial. CONCLUSION Although this study has drawbacks that limit interpretation, the data support the use of single-use Btx A vials in multiple patients. Whereas adverse events may occur due to Btx A side effects and percutaneous injections, there does not seem to be any indication that these are infection related. Furthermore, the storage of reconstituted Btx A for longer than the recommended 4 hours does not limit the efficacy of the product. Singleuse Btx A is both safe and effective despite using it in multiple patients and refrigerating and storing it at 4 C for longer than the recommended time. BIBLIOGRAPHY 1. Ting PT, Freiman A. The story of Clostridium botulinum: from food poisoning to Botox. Clin Med 2004;4: Thomas JP, Siupsinskiene N. Frozen versus fresh reconstituted botox for laryngeal dystonia. Otolaryngol Head Neck Surg 2006;135: Persaud R, Garas G, Silva S, Stamatoglou C, Chatrath P, Patel K. An evidence-based review of botulinum toxin (Botox) applications in noncosmetic head and neck conditions. JRSM Short Rep 2013;4: Botox [package insert]. Irvine, CA: Allergan Inc.; Liu A, Carruthers A, Cohen JL, et al. Recommendations and current practices for the reconstitution and storage of botulinum toxin type A. JAm Acad Dermatol 2012;67: Centers for Disease Control and Prevention. Protect patients against preventable harm from improper use of single dose/single use vials. 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6 14. Hexsel DM, De Almeida AT, Rutowitsch M, et al., Multicenter, doubleblind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003;29: ; discussion Parsa AA, Lye KD, Parsa FD. Reconstituted botulinum type A neurotoxin: clinical efficacy after long-term freezing before use. Aesthetic Plast Surg 2007;31: ; discussion Lizarralde M, Gutierrez SH, Venegas A. Clinical efficacy of botulinum toxin type A reconstituted and refrigerated 1 week before its application in external canthus dynamic lines. Dermatol Surg 2007;33: ; discussion Hexsel D, Rutowitsch MS, de Castro LC, do Prado DZ, Lima MM. Blind multicenter study of the efficacy and safety of injections of a commercial preparation of botulinum toxin type A reconstituted up to 15 days before injection. Dermatol Surg 2009;35: ; discussion Menon J, Murray A. Microbial growth in vials of Botulinum toxin following use in clinic. Eye (Lond) 2007;21: Alam M, Yoo SS, Wrone DA, White LE, Kim JY. Sterility assessment of multiple use botulinum A exotoxin vials: a prospective simulation. JAm Acad Dermatol 2006;55: Shah MD, Johns MM III. Office-based botulinum toxin injections. Otolaryngol Clin North Am 2013;46: Blitzer A, Brin MF, Stewart CF. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope 1998;108: Klein AW. Contraindications and complications with the use of botulinum toxin. Clin Dermatol 2004;22: Brin MF, Boodhoo TI, Pogoda JM, et al., Safety and tolerability of onabotulinumtoxina in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants. J Am Acad Dermatol 2009;61: e1 e Cote TR, Mohan AK, Polder JA, Walton MK, Braun MM. Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. J Am Acad Dermatol 2005;53: