- Email: [email protected]
IncobotulinumtoxinA for Migraine: A Retrospective Case Series
Clinical Therapeutics/Volume ], Number ], 2015
Case Report
IncobotulinumtoxinA for Migraine: A Retrospective Case Series Rashid Kazerooni, PharmD, BCPS1,2; Jane Lim, BS1,2; Ashley Blake PharmD1,2; and Stephanie Lessig, MD1,2 1
Veterans Affairs San Diego Healthcare System, San Diego, California; and 2University of California San Diego, San Diego, CA
ABSTRACT Purpose: IncobotulinumtoxinA is used for treating certain movement disorders but lacks published clinical data on use in chronic migraine. Methods: This retrospective case series was performed by using electronic chart reviews on patients receiving incobotulinumtoxinA for migraine at the Veterans Affairs San Diego Healthcare System between September 2013 and March 2014. Patients were administered 150 units each, with similar methods used for onabotulinumtoxinA injections. Findings: A total of 21 patients were included in the analysis. Patients were 40 years old on average, 67% white, and 52% female. Patients had trialed an average of 4.19 oral prophylactic agents for migraine with 43% having previous history of onabotulinumtoxinA use and 29% having a history of traumatic brain injury. Patients reported a decrease in headache days per month (19.1 vs 9.1; P o 0.001) and headache intensity (8.3 vs 4.1; P o 0.001) after incobotulinumtoxinA injections. Most patients experienced an improvement in headache frequency and/or intensity (81.8%). The duration of action for these patients averaged 81.9 days (median, 70 days). Implications: Significant improvements in headache frequency and intensity were observed. Chronic migraine is not an indication approved by the US Food and Drug Administration for incobotulinumtoxinA; however, the drug’s effectiveness was documented in this small patient population. (Clin Ther. 2015;]:]]]– ]]]) Published by Elsevier HS Journals, Inc. Key words: botulinum, headache, migraine, toxin, Xeomin.
is often accompanied by financial and social burdens and decreases the overall quality of life.3 According to the International Classification of Headache Disorders, chronic migraine is defined as headache on 415 days per month for at least 3 months, with 48 days fulfilling criteria for pain and associated symptoms of migraine without aura.4 Although oral medications are used for migraine prophylaxis, none are indicated for use in chronic migraine. Currently, botulinum toxin type A (onabotulinumtoxinA)* is the only approved botulinum toxin indicated for the prophylaxis of headaches in adult patients with chronic migraine.5,6 In 2 large, Phase III, placebo-controlled trials (PREEMPT [Phase III Research Evaluating Migraine Prophylaxis Therapy]), the efficacy and safety of onabotulinumtoxinA were evaluated in 1005 patients with chronic migraine for a total of 24 weeks, including an open-label extension to 56 weeks. Patients experienced significantly greater reductions in frequency of headache days and treatment-related adverse effects.7 Botulinum toxin is a neurotoxin produced by the anaerobic bacterium, Clostridium botulinum. The mechanism that has been best studied is its ability to block acetylcholine release at the neuromuscular junction and cause muscle relaxation.8 However, its analgesic effect is less well understood. The trigeminovascular pathway is believed to be a main factor during a migraine attack. Using electrophysiological techniques, Burstein et al9 demonstrated the ability of botulinum toxin A to inhibit mechanical nociception in peripheral trigeminovascular neurons. Trademark: Botoxs (Allergan, Parsippany, New Jersey).
*
INTRODUCTION
Headache disorders are estimated to occur in 440% of the adult population.1,2 This common disabling condition
] 2015
Accepted for publication May 29, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.509 0149-2918/$ - see front matter Published by Elsevier HS Journals, Inc.
1
Clinical Therapeutics Although onabotulinumtoxinA’s mechanism of action regarding its use for headache prophylaxis in chronic migraine patients is not fully understood, it is still the most well-studied botulinum toxin reported on in the literature. Conversely, incobotulinumtoxinA† has been used for treating certain movement disorders but lacks any clinical data on its therapeutic use for chronic migraine. IncobotulinumtoxinA is considered approximately equipotent to onabotulinumtoxinA on a unit-tounit basis.10 In addition, a recent analysis suggested that incobotulinumtoxinA may have a more rapid onset and longer duration of action compared with onabotulinumtoxinA.11 The goal of the present case report was to provide initial data regarding an alternative botulinum agent in the treatment of chronic migraine.
MATERIALS AND METHODS This retrospective case series was performed by using electronic medical record chart reviews on patients receiving incobotulinumtoxinA for migraine at the Veterans Affairs San Diego Healthcare System between September 2013 and March 2014. Currently, the recommended total starting dose of onabotulinumtoxinA is 155 units per injection cycle for the treatment of chronic migraine; this amount may be titrated up to 195 units. It is only supplied in a singleuse vial in 100 or 200 units, resulting in 45 units of wastage per patient at the starting dose (which is the most commonly used dose at our facility).6 Conversely, incobotulinumtoxinA is supplied in 50or 100-unit vials. Due to price differences between products attributable to costs per unit as well as wastage with onabotulinumtoxinA, a local policy was implemented in September 2013 that gave neurology providers a choice between the 2 agents, primarily for new starts. Formulary guidelines at the facility required a minimum trial of 4 previous oral formulary prophylactic agents before the use of botulinum toxin. IncobotulinumtoxinA patients had orders for 150 units per patient for treatment, with similar methods (31 set injection sites) used for onabotulinumtoxinA injections, with zero wastage. Dosing was therefore similar but not equivalent with onabotulinumtoxinA’s 155 unit starting dose approved by the US Food and †
Trademark: Xeomins (Merz Pharmaceuticals, LLC, Raleigh, North Carolina).
2
Drug Administration. Follow-up was typically 3 months after initial injection. Patients were excluded from the analysis if they were missing baseline or follow-up headache frequency data in the notes. The primary outcome was reduction in headache days per month as self-reported by the patient. The secondary outcome was reduction in headache intensity as well as a binomial outcome of any improvement, defined as any improvement in headache day frequency or intensity. Headache intensity was defined as the average headache intensity subjectively reported by the patient on a 0 to 10 numeric rating scale, a validated 1-dimensional pain scale.12 The duration of action before any wear-off of the medication was also assessed. All outcomes were evaluated after the first injection of incobotulinumtoxinA. A paired sample t test was performed by using Excel (Microsoft Corporation, Redmond, Washington) to determine differences in headache frequency and intensity. Because data were taken retrospectively from electronic medical records, bias in reporting was not considered an issue.
RESULTS A total of 29 patients received incobotulinumtoxinA injections for chronic migraine. Eight patients were excluded due to lack of documentation regarding frequency of headache days, leaving 21 patients in the final analysis. Of the 21 patients, 12 also had both preinjection and postinjection scores for headache intensity. Patients were, on average, 40 years of age, white, and previously failed to respond to at least 4 oral prophylactic medications (Table I). Eleven of the 21 patients were female. Patients reported a decrease in headache days per month (19.1 vs 9.1 days; P o 0.001) and headache intensity (8.3 vs 4.1; P o 0.001) after incobotuliumtoxinA injections (Figure, Table II). Most patients experienced an improvement in headache frequency and/or intensity (81.8%). The duration of action for these patients averaged 81.9 days (median, 70 days), and the average time to followup was 90.7 days. No discernible difference was found between male and female subjects in outcomes, as 8 of 10 men and 9 of 11 women received at least some improvement with therapy. In patients previously not treated with onabotulinumtoxinA, 8 of 12 reported improvement, whereas all 9 previously treated patients
Volume ] Number ]
R. Kazerooni et al.
Table I. Baseline demographic characteristics (N ¼ 21). Unless otherwise indicated, values are number (%). Characteristic
Value
Age, mean (SD), y Ethnicity, Hispanic Race White African American Asian American Indian Unknown Oral prophylactic medications trialed, mean (SD) Prior use of botulinum toxin type A Traumatic brain injury
40 (9.5) 3 (14.3) 14 4 1 1 1 4.19
(66.7) (19.0) (4.8) (4.8) (4.8) (1.25)
9 (42.9) 6 (28.6)
experienced improvement. However, there were no differences in reductions in headache days per month or headache intensity for patients previously treated with onabotulinumtoxinA versus previously untreated patients. For patients with traumatic brain injury, 5 of 6 reported improvement from therapy (mean decrease in headache days per month, 19.5 to 6.7) compared with 12 of 15 of nontraumatic brain injury patients (mean decrease in headache days per month, 18.9 to 10.1). No adverse events were documented for any patient.
DISCUSSION Significant improvements in headache days per month and headache intensity were observed with the use of incobotulinumtoxinA in patients who had failed to respond to 4 previous oral prophylactic agents. IncobotulinumtoxinA is currently approved for the treatment of cervical dystonia, blepharospasm in adults previously treated with onabotulinumtoxinA, and the temporary correction of glabellar lines in adults.13 Although the treatment for adults with chronic migraine is not an indication of incobotulinumtoxinA approved by the US Food and Drug Administration, its efficacy was documented in our small patient population. Several patients noted the wearing off of medication 2 weeks before the 3-month follow-up period. A limitation to this outcome is that observations to assess the duration of action were only noted once during the follow-up appointments and were based on the patients’ subjective reporting. In the Phase III studies assessing the efficacy and safety of onabotulinumtoxinA, the primary outcome was mean change from baseline in the frequency of headache days at 24 weeks after 2 injections.7 Headache day frequency and intensity in the present study were measured after 1 injection, typically after 12 weeks. These results cannot be extrapolated and should be assessed with caution. Although direct comparisons to onabotulinumtoxinA cannot be made in the treatment of chronic migraine, duration of action is an important factor that can affect the regimen and overall satisfaction in a patient’s medication management.
30
Headache Days Per Month
25 20 15 10 5 0 Preinjection
Postinjection
Figure. Individual patient outcomes.
] 2015
3
Clinical Therapeutics
Table II. Primary and secondary outcomes. IncobotulinumtoxinA Injections Variable
Preinjection
Postinjection
P
18.0 8.1 —
8.7 4.2 17 (81.0)
o0.001 o0.001
— —
81.9 (27.5) 70.0
Headache days per month (N ¼ 21) Headache intensity* (n ¼ 10) Any improvement, no. (%) (N ¼ 21) Duration of action, d (n ¼ 17) Mean (SD) Median *
On a scale of 1 to 10.
IncobotulinumtoxinA’s smallest manufactured package size (50-unit vials) is smaller than that of onabotulinumtoxinA (100 units). Manufacturer recommendations are to not share vials between patients for onabotulinumtoxinA, resulting in 45 units of wastage per patient assuming a 155-unit dose (22.5% wastage). Using incobotulinumtoxinA at 150 units per patient brings the wastage down to zero. A recent cost-effectiveness analysis comparing 3 different botulinum toxin products in a different indication (cervical dystonia) found that incobotulinumtoxinA was the most cost-effective agent, in large part because of the reduced wastage associated with its use.14 Health care systems facing constrained budgets are often open to novel ideas to reduce cost and waste without sacrificing clinical care. Due to the nature of a case series, a limitation of the present study was its small sample size. An additional limitation was the retrospective nature of this analysis. A larger study investigating incobotulinumtoxinA for this indication would reveal greater validity in results. Because the treatment of chronic migraine requires repeated injections, the long-term safety and efficacy of incobotulinumtoxinA should be investigated. Due to the higher prevalence of traumatic brain injury in this veteran population, generalizing these results outside of a veteran population is not recommended.
CONCLUSIONS
To our knowledge, this study is one of the first published analyses investigating the effect of incobotuliumtoxinA on patients with chronic migraine. IncobotuliumtoxinA
4
was found to be effective in our small population, and its lower cost and wastage compared with those of onabotulinumtoxinA may be appealing for health systems with growing budgetary constraints. However, direct comparisons to onabotulinumtoxinA cannot be made. Future larger randomized controlled studies should investigate these agents head-to-head in a variety of indications, including chronic migraine.
ACKNOWLEDGMENTS The authors thank the Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego for the summer research grant which funded the work of the research assistant. Dr. Kazerooni contributed literature review, study design, data collection, data interpretation, and manuscript writing. Jane Lim, research assistant, contributed literature review, manuscript writing, and table/ figure creation. Dr. Lessig contributed expert opinion, manuscript feedback, and data interpretation.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
REFERENCES 1. Headache Disorders. WHO. Web. Accessed 8 Aug 2014 http://www.who.int/mediacentre/factsheets/fs277/en/. 2. QuickStats: Percentage of Adults Who Had Migraines or Severe Headaches, Pain in the Neck, Lower Back, or Face/ Jaw, by Sex—National Health Interview Survey, 2009. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 03 Dec. 2010. Web.
Volume ] Number ]
R. Kazerooni et al.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Accessed 8 Aug 2014. http://www. cdc.gov/mmwr/preview/mmwrhtml/ mm5947a6.htm. Stovner LJ, Al Jumah M, Birbeck GL, et al. The methodology of population surveys of headache prevalence, burden and cost: principles and recommendations from the Global Campaign against Headache. J Headache Pain. 2014;15:5. Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia. 2006;26:6742–6746. Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group. Headache. 2000;40:445–450. Allergan Inc. BOTOX (onabotulinumA) Full Prescribing Information. Irvine, CA: Allergan Inc; 2013. Aurora SK, Dodick DW, Diener HC, et al. OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta Neurol Scand. 2014;129:61–70. Ashkenazi A, Silberstein SD. Botulinum toxin and other new approaches to migraine therapy. Annu Rev Med. 2004;55:505–518. Burstein R, Zhang X, Levy D, et al. Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: therapeutic implications for migraine and other pains. Cephalalgia. 2014;34:853–869. Jandhyala R. Relative potency of incobotulinumtoxinA vs onabotulinumtoxinA a meta-analysis of key evidence. J Drugs Dermatol. 2012;11:731–736. Rappl T, Parvizi D, Friedl H, et al. Onset and duration of effect of incobotulinumtoxinA, onabotulinumtoxinA, and abobotulinumtoxinA in the treatment of glabellar frown lines: a randomized, double-blind study. Clin Cosmet Investig Dermatol. 2013;6:211–219. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing numerical
] 2015
rating scales, verbal rating scales, and visual analog scales for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage. 2011;41:1073–1093. 13. Merz Pharmaceuticals. Xeomin (incobotulinumtoxinA) Full prescribing information.
Greensboro, NC: Merz Pharmaceuticals, LLC; 2014. 14. Kazerooni R, Broadhead C. Cost utility analysis of botulinum toxin type A products for the treatment of cervical dystonia. Am J Health Syst Pharm. 2015;72:301–307.
Address correspondence to: Rashid Kazerooni, PharmD, BCPS, Pharmacoeconomics Program Manager, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive (119), San Diego, CA 92161. E-mail: [email protected]
5
Case Report
IncobotulinumtoxinA for Migraine: A Retrospective Case Series Rashid Kazerooni, PharmD, BCPS1,2; Jane Lim, BS1,2; Ashley Blake PharmD1,2; and Stephanie Lessig, MD1,2 1
Veterans Affairs San Diego Healthcare System, San Diego, California; and 2University of California San Diego, San Diego, CA
ABSTRACT Purpose: IncobotulinumtoxinA is used for treating certain movement disorders but lacks published clinical data on use in chronic migraine. Methods: This retrospective case series was performed by using electronic chart reviews on patients receiving incobotulinumtoxinA for migraine at the Veterans Affairs San Diego Healthcare System between September 2013 and March 2014. Patients were administered 150 units each, with similar methods used for onabotulinumtoxinA injections. Findings: A total of 21 patients were included in the analysis. Patients were 40 years old on average, 67% white, and 52% female. Patients had trialed an average of 4.19 oral prophylactic agents for migraine with 43% having previous history of onabotulinumtoxinA use and 29% having a history of traumatic brain injury. Patients reported a decrease in headache days per month (19.1 vs 9.1; P o 0.001) and headache intensity (8.3 vs 4.1; P o 0.001) after incobotulinumtoxinA injections. Most patients experienced an improvement in headache frequency and/or intensity (81.8%). The duration of action for these patients averaged 81.9 days (median, 70 days). Implications: Significant improvements in headache frequency and intensity were observed. Chronic migraine is not an indication approved by the US Food and Drug Administration for incobotulinumtoxinA; however, the drug’s effectiveness was documented in this small patient population. (Clin Ther. 2015;]:]]]– ]]]) Published by Elsevier HS Journals, Inc. Key words: botulinum, headache, migraine, toxin, Xeomin.
is often accompanied by financial and social burdens and decreases the overall quality of life.3 According to the International Classification of Headache Disorders, chronic migraine is defined as headache on 415 days per month for at least 3 months, with 48 days fulfilling criteria for pain and associated symptoms of migraine without aura.4 Although oral medications are used for migraine prophylaxis, none are indicated for use in chronic migraine. Currently, botulinum toxin type A (onabotulinumtoxinA)* is the only approved botulinum toxin indicated for the prophylaxis of headaches in adult patients with chronic migraine.5,6 In 2 large, Phase III, placebo-controlled trials (PREEMPT [Phase III Research Evaluating Migraine Prophylaxis Therapy]), the efficacy and safety of onabotulinumtoxinA were evaluated in 1005 patients with chronic migraine for a total of 24 weeks, including an open-label extension to 56 weeks. Patients experienced significantly greater reductions in frequency of headache days and treatment-related adverse effects.7 Botulinum toxin is a neurotoxin produced by the anaerobic bacterium, Clostridium botulinum. The mechanism that has been best studied is its ability to block acetylcholine release at the neuromuscular junction and cause muscle relaxation.8 However, its analgesic effect is less well understood. The trigeminovascular pathway is believed to be a main factor during a migraine attack. Using electrophysiological techniques, Burstein et al9 demonstrated the ability of botulinum toxin A to inhibit mechanical nociception in peripheral trigeminovascular neurons. Trademark: Botoxs (Allergan, Parsippany, New Jersey).
*
INTRODUCTION
Headache disorders are estimated to occur in 440% of the adult population.1,2 This common disabling condition
] 2015
Accepted for publication May 29, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.509 0149-2918/$ - see front matter Published by Elsevier HS Journals, Inc.
1
Clinical Therapeutics Although onabotulinumtoxinA’s mechanism of action regarding its use for headache prophylaxis in chronic migraine patients is not fully understood, it is still the most well-studied botulinum toxin reported on in the literature. Conversely, incobotulinumtoxinA† has been used for treating certain movement disorders but lacks any clinical data on its therapeutic use for chronic migraine. IncobotulinumtoxinA is considered approximately equipotent to onabotulinumtoxinA on a unit-tounit basis.10 In addition, a recent analysis suggested that incobotulinumtoxinA may have a more rapid onset and longer duration of action compared with onabotulinumtoxinA.11 The goal of the present case report was to provide initial data regarding an alternative botulinum agent in the treatment of chronic migraine.
MATERIALS AND METHODS This retrospective case series was performed by using electronic medical record chart reviews on patients receiving incobotulinumtoxinA for migraine at the Veterans Affairs San Diego Healthcare System between September 2013 and March 2014. Currently, the recommended total starting dose of onabotulinumtoxinA is 155 units per injection cycle for the treatment of chronic migraine; this amount may be titrated up to 195 units. It is only supplied in a singleuse vial in 100 or 200 units, resulting in 45 units of wastage per patient at the starting dose (which is the most commonly used dose at our facility).6 Conversely, incobotulinumtoxinA is supplied in 50or 100-unit vials. Due to price differences between products attributable to costs per unit as well as wastage with onabotulinumtoxinA, a local policy was implemented in September 2013 that gave neurology providers a choice between the 2 agents, primarily for new starts. Formulary guidelines at the facility required a minimum trial of 4 previous oral formulary prophylactic agents before the use of botulinum toxin. IncobotulinumtoxinA patients had orders for 150 units per patient for treatment, with similar methods (31 set injection sites) used for onabotulinumtoxinA injections, with zero wastage. Dosing was therefore similar but not equivalent with onabotulinumtoxinA’s 155 unit starting dose approved by the US Food and †
Trademark: Xeomins (Merz Pharmaceuticals, LLC, Raleigh, North Carolina).
2
Drug Administration. Follow-up was typically 3 months after initial injection. Patients were excluded from the analysis if they were missing baseline or follow-up headache frequency data in the notes. The primary outcome was reduction in headache days per month as self-reported by the patient. The secondary outcome was reduction in headache intensity as well as a binomial outcome of any improvement, defined as any improvement in headache day frequency or intensity. Headache intensity was defined as the average headache intensity subjectively reported by the patient on a 0 to 10 numeric rating scale, a validated 1-dimensional pain scale.12 The duration of action before any wear-off of the medication was also assessed. All outcomes were evaluated after the first injection of incobotulinumtoxinA. A paired sample t test was performed by using Excel (Microsoft Corporation, Redmond, Washington) to determine differences in headache frequency and intensity. Because data were taken retrospectively from electronic medical records, bias in reporting was not considered an issue.
RESULTS A total of 29 patients received incobotulinumtoxinA injections for chronic migraine. Eight patients were excluded due to lack of documentation regarding frequency of headache days, leaving 21 patients in the final analysis. Of the 21 patients, 12 also had both preinjection and postinjection scores for headache intensity. Patients were, on average, 40 years of age, white, and previously failed to respond to at least 4 oral prophylactic medications (Table I). Eleven of the 21 patients were female. Patients reported a decrease in headache days per month (19.1 vs 9.1 days; P o 0.001) and headache intensity (8.3 vs 4.1; P o 0.001) after incobotuliumtoxinA injections (Figure, Table II). Most patients experienced an improvement in headache frequency and/or intensity (81.8%). The duration of action for these patients averaged 81.9 days (median, 70 days), and the average time to followup was 90.7 days. No discernible difference was found between male and female subjects in outcomes, as 8 of 10 men and 9 of 11 women received at least some improvement with therapy. In patients previously not treated with onabotulinumtoxinA, 8 of 12 reported improvement, whereas all 9 previously treated patients
Volume ] Number ]
R. Kazerooni et al.
Table I. Baseline demographic characteristics (N ¼ 21). Unless otherwise indicated, values are number (%). Characteristic
Value
Age, mean (SD), y Ethnicity, Hispanic Race White African American Asian American Indian Unknown Oral prophylactic medications trialed, mean (SD) Prior use of botulinum toxin type A Traumatic brain injury
40 (9.5) 3 (14.3) 14 4 1 1 1 4.19
(66.7) (19.0) (4.8) (4.8) (4.8) (1.25)
9 (42.9) 6 (28.6)
experienced improvement. However, there were no differences in reductions in headache days per month or headache intensity for patients previously treated with onabotulinumtoxinA versus previously untreated patients. For patients with traumatic brain injury, 5 of 6 reported improvement from therapy (mean decrease in headache days per month, 19.5 to 6.7) compared with 12 of 15 of nontraumatic brain injury patients (mean decrease in headache days per month, 18.9 to 10.1). No adverse events were documented for any patient.
DISCUSSION Significant improvements in headache days per month and headache intensity were observed with the use of incobotulinumtoxinA in patients who had failed to respond to 4 previous oral prophylactic agents. IncobotulinumtoxinA is currently approved for the treatment of cervical dystonia, blepharospasm in adults previously treated with onabotulinumtoxinA, and the temporary correction of glabellar lines in adults.13 Although the treatment for adults with chronic migraine is not an indication of incobotulinumtoxinA approved by the US Food and Drug Administration, its efficacy was documented in our small patient population. Several patients noted the wearing off of medication 2 weeks before the 3-month follow-up period. A limitation to this outcome is that observations to assess the duration of action were only noted once during the follow-up appointments and were based on the patients’ subjective reporting. In the Phase III studies assessing the efficacy and safety of onabotulinumtoxinA, the primary outcome was mean change from baseline in the frequency of headache days at 24 weeks after 2 injections.7 Headache day frequency and intensity in the present study were measured after 1 injection, typically after 12 weeks. These results cannot be extrapolated and should be assessed with caution. Although direct comparisons to onabotulinumtoxinA cannot be made in the treatment of chronic migraine, duration of action is an important factor that can affect the regimen and overall satisfaction in a patient’s medication management.
30
Headache Days Per Month
25 20 15 10 5 0 Preinjection
Postinjection
Figure. Individual patient outcomes.
] 2015
3
Clinical Therapeutics
Table II. Primary and secondary outcomes. IncobotulinumtoxinA Injections Variable
Preinjection
Postinjection
P
18.0 8.1 —
8.7 4.2 17 (81.0)
o0.001 o0.001
— —
81.9 (27.5) 70.0
Headache days per month (N ¼ 21) Headache intensity* (n ¼ 10) Any improvement, no. (%) (N ¼ 21) Duration of action, d (n ¼ 17) Mean (SD) Median *
On a scale of 1 to 10.
IncobotulinumtoxinA’s smallest manufactured package size (50-unit vials) is smaller than that of onabotulinumtoxinA (100 units). Manufacturer recommendations are to not share vials between patients for onabotulinumtoxinA, resulting in 45 units of wastage per patient assuming a 155-unit dose (22.5% wastage). Using incobotulinumtoxinA at 150 units per patient brings the wastage down to zero. A recent cost-effectiveness analysis comparing 3 different botulinum toxin products in a different indication (cervical dystonia) found that incobotulinumtoxinA was the most cost-effective agent, in large part because of the reduced wastage associated with its use.14 Health care systems facing constrained budgets are often open to novel ideas to reduce cost and waste without sacrificing clinical care. Due to the nature of a case series, a limitation of the present study was its small sample size. An additional limitation was the retrospective nature of this analysis. A larger study investigating incobotulinumtoxinA for this indication would reveal greater validity in results. Because the treatment of chronic migraine requires repeated injections, the long-term safety and efficacy of incobotulinumtoxinA should be investigated. Due to the higher prevalence of traumatic brain injury in this veteran population, generalizing these results outside of a veteran population is not recommended.
CONCLUSIONS
To our knowledge, this study is one of the first published analyses investigating the effect of incobotuliumtoxinA on patients with chronic migraine. IncobotuliumtoxinA
4
was found to be effective in our small population, and its lower cost and wastage compared with those of onabotulinumtoxinA may be appealing for health systems with growing budgetary constraints. However, direct comparisons to onabotulinumtoxinA cannot be made. Future larger randomized controlled studies should investigate these agents head-to-head in a variety of indications, including chronic migraine.
ACKNOWLEDGMENTS The authors thank the Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego for the summer research grant which funded the work of the research assistant. Dr. Kazerooni contributed literature review, study design, data collection, data interpretation, and manuscript writing. Jane Lim, research assistant, contributed literature review, manuscript writing, and table/ figure creation. Dr. Lessig contributed expert opinion, manuscript feedback, and data interpretation.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
REFERENCES 1. Headache Disorders. WHO. Web. Accessed 8 Aug 2014 http://www.who.int/mediacentre/factsheets/fs277/en/. 2. QuickStats: Percentage of Adults Who Had Migraines or Severe Headaches, Pain in the Neck, Lower Back, or Face/ Jaw, by Sex—National Health Interview Survey, 2009. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 03 Dec. 2010. Web.
Volume ] Number ]
R. Kazerooni et al.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Accessed 8 Aug 2014. http://www. cdc.gov/mmwr/preview/mmwrhtml/ mm5947a6.htm. Stovner LJ, Al Jumah M, Birbeck GL, et al. The methodology of population surveys of headache prevalence, burden and cost: principles and recommendations from the Global Campaign against Headache. J Headache Pain. 2014;15:5. Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia. 2006;26:6742–6746. Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group. Headache. 2000;40:445–450. Allergan Inc. BOTOX (onabotulinumA) Full Prescribing Information. Irvine, CA: Allergan Inc; 2013. Aurora SK, Dodick DW, Diener HC, et al. OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta Neurol Scand. 2014;129:61–70. Ashkenazi A, Silberstein SD. Botulinum toxin and other new approaches to migraine therapy. Annu Rev Med. 2004;55:505–518. Burstein R, Zhang X, Levy D, et al. Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: therapeutic implications for migraine and other pains. Cephalalgia. 2014;34:853–869. Jandhyala R. Relative potency of incobotulinumtoxinA vs onabotulinumtoxinA a meta-analysis of key evidence. J Drugs Dermatol. 2012;11:731–736. Rappl T, Parvizi D, Friedl H, et al. Onset and duration of effect of incobotulinumtoxinA, onabotulinumtoxinA, and abobotulinumtoxinA in the treatment of glabellar frown lines: a randomized, double-blind study. Clin Cosmet Investig Dermatol. 2013;6:211–219. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing numerical
] 2015
rating scales, verbal rating scales, and visual analog scales for assessment of pain intensity in adults: a systematic literature review. J Pain Symptom Manage. 2011;41:1073–1093. 13. Merz Pharmaceuticals. Xeomin (incobotulinumtoxinA) Full prescribing information.
Greensboro, NC: Merz Pharmaceuticals, LLC; 2014. 14. Kazerooni R, Broadhead C. Cost utility analysis of botulinum toxin type A products for the treatment of cervical dystonia. Am J Health Syst Pharm. 2015;72:301–307.
Address correspondence to: Rashid Kazerooni, PharmD, BCPS, Pharmacoeconomics Program Manager, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive (119), San Diego, CA 92161. E-mail: [email protected]
5