J Neural Transm (2015) 122:327–333 DOI 10.1007/s00702-014-1252-9
PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE
Safety aspects of incobotulinumtoxinA high-dose therapy Dirk Dressler • Fereshte Adib Saberi Katja Kollewe • Christoph Schrader
•
Received: 28 February 2014 / Accepted: 25 May 2014 / Published online: 17 July 2014 Ó Springer-Verlag Wien 2014
Abstract Botulinum toxin (BT) used for dystonia and spasticity is dosed according to the number of target muscles and the severity of their muscle hyperactivities. With this no other drug is used in a broader dose range than BT. The upper end of this range, however, still needs to be explored. We wanted to do this by a prospective noninterventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (XeominÒ) high-dose therapy (HD group, n = 100, single dose C400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose B200 MU). At the measurement point all patients were evaluated for systemic BT toxicity, i.e. systemic motor impairment or systemic autonomic dysfunction. HD group patients (56.1 ± 13.8 years, 46 dystonia, 54 spasticity) were treated with XeominÒ 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. In dystonia patients the number of target muscles was 46 and the dose per target muscle 56.4 ± 19.1 MU, in spasticity patients 35 and 114.9 ± 67.1 MU. HD and RD group patients reported 58 occurrences of items on the systemic toxicity questionnaire. Generalised weakness, being bedridden, feeling of residual urine and constipation were caused by the underlying tetra- or paraparesis, blurred vision by presbyopia. Dysphagia and dryness of eye were local BT adverse effects. Neurologic examination, serum chemistry and full blood count did not indicate any systemic adverse effects. Elevated serum levels for creatine kinase/MB, creatine
D. Dressler (&) F. Adib Saberi K. Kollewe C. Schrader Movement Disorders Section, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany e-mail: [email protected]
kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibodyinduced therapy failure. XeominÒ can be used safely in doses C400 MU and up to 1,200 MU without detectable systemic toxicity. This allows expanding the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies—carefully designed and rigorously monitored—are necessary to explore the threshold dose for clinically detectable systemic toxicity. Keywords Botulinum toxin Therapeutic use Highdose therapy Safety Systemic toxicity Antibody formation
Introduction Over the last 30 years botulinum toxin (BT) has gained widespread use for the treatment of numerous medical conditions caused by overactive muscles or overactive exocrine glands (Truong et al. 2009). Its use for treatment of non-motor pain is currently investigated (Aurora et al. 2011). No other drug is used in a broader range dose. In registered indications recommended single doses start from 20 MU of onabotulinumtoxinA (BotoxÒ, VistabelÒ, Botox CosmeticÒ) (VistabelÒ: Summary of Product Characteristics 2013) or 20 MU of incobotulinumtoxinA (XeominÒ, BocoutureÒ) (BocoutureÒ: Summary of Product Characteristics 2013) for glabella lines to BotoxÒ 300 MU for cervical dystonia (BotoxÒ: Summary of Product Characteristics 2013) or XeominÒ 400 MU for arm spasticity after stroke (XeominÒ: Summary of Product Characteristics 2013). Under off-label use conditions even lower single
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doses of BotoxÒ 1.25 MU (Rosow et al. 2013) have been used for spasmodic dysphonia. The upper end of the therapeutic dose range, however, still needs to be explored. Maximal recommended single doses of around BotoxÒ 400 MU or XeominÒ 400 MU allow to inject only a limited number of target muscles thus preventing exploiting the full potential of BT therapy. Since current dose recommendations are not based on any negative safety data, we felt encouraged to gradually increase the maximal single doses in our clinical practice over the last years under careful monitoring of systemic toxicity and the occurrence of antibody-induced complete secondary therapy failure (CSTF). This study summarises our experience with the safety of XeominÒ high-dose therapy.
(5) body weight C50 kg. Exclusion criteria: (1) inability to cooperate; (2) conditions affecting the normal neuromuscular junction functioning; (3) Conditions potentially able to produce fatigue such as multiple sclerosis or cancer. (4) drugs affecting the autonomic nervous system such as anticholinergics; (5) peripherally acting antispastic drugs such as dantrolene; (6) continuous intrathecal baclofen pumps. Other oral antispastic drugs were allowed when doses were stable for at least 6 months prior to the measurement point. Anticoagulation was allowed, but recent INR values had to be provided. For the RD group 30 patients fulfilling identical inclusion and exclusion criteria as patients in the HD group were randomly selected. The only difference was that their single dose was XeominÒ B200 MU.
Methods
Botulinum toxin drugs
Definitions
All patients were treated with XeominÒ at the measurement point and for the previous two injection series. Before this, BotoxÒ and abobotulinumtoxinA (DysportÒ) may have been applied. XeominÒ was reconstituted with 2.5 ml 0.9 % NaCl/H2O.
Single dose is the amount of BT given at each injection series. Injection series is the application of BT on one given day. Measurement point is the time when the patient is evaluated by STQ. Observation period is the time from the first BT application in our clinics to the measurement point. Inter-injection interval is the time between two subsequent injection series. Target muscle is a muscle receiving BT. Treatment cycle is the BT application with the subsequent time period until the next injection series. Design The study followed a prospective non-interventional design comparing the study group receiving XeominÒ high-dose therapy (HD group) to a control group receiving XeominÒ regular-dose therapy (RD group). At the measurement point all patients in the HD group and in the RD group were evaluated for the study parameter, i.e. systemic toxicity manifesting as dysfunction of the motor system and the autonomic nervous system distant from the injection site. Additional study parameter was the occurrence of CSTF. All findings in the HD group were compared to those in the RD group. Patients All patients were recruited from our BT outpatient clinics. Treatment data of all patients receiving BT treatment are stored in a digital data base. For the HD group 100 patients fulfilling the following inclusion and exclusion criteria were randomly selected. Inclusion criteria: (1) single dose CXeominÒ 400 MU; (2) number of injection series C4; (3) various forms of dystonia or spasticity; (4) age C 18 years;
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Botulinum toxin therapy XeominÒ was dosed according to the individual symptomatology and dose modifiers in an algorithm developed by us over the last 25 years. All XeominÒ dose C500 MU were titrated over several subsequent injection series. Interinjection intervals were generally set to 12 weeks. If necessary, shortened inter-injection intervals could be used. The minimum inter-injection interval allowed was 10 weeks. XeominÒ was applied clinically. Where necessary, ultrasound guidance or electromyographic guidance (including electrostimulation) was used. XeominÒ doses for each target muscle were distributed to several injection sites, so that the volume per injection site was around 0.5 ml. Evaluation Systemic toxicity was evaluated by STQ, NE and LS. The STQ was developed based on our previous observations on the systemic toxicity of BT type B (Dressler and Benecke 2003). Details are shown in Table 1 (see ‘‘Results’’). Patients were asked whether any of the items occurred during the last two injection series. It was also documented whether the occurrence could be explained by an underlying condition or a local BT adverse effect and whether it was compatible with the time course of the BT action. NE tested the BT effect on the target muscle. It also included examination of muscle strength on acute maximal activation and muscle fatigue on repeated activations in selected
Safety aspects of incobotulinumtoxinA high-dose therapy
muscles distant from the target muscles. Additionally, cranial nerve function including pupillomotor function and double vision, as well as the moisture of skin, oral mucosa and eyes were tested. LS were performed when the patient received BT re-injections. It included chemistry, enzymes and full blood count. Details are shown in Table 2 (see ‘‘Results’’). CSTF was evaluated by the criteria previously described by us (Dressler 2004a, b). They include initially sufficient BT effects, subsequently shortened durations of action and complete lack of BT efficacy on three subsequent BT injection series. If there was CSTF, BT antibody titres were studied using the mouse hemidiaphragm assay (Go¨schel et al. 1997) provided by Toxogen, Hannover, Germany. Randomisation Randomisation was performed by random.org (Randomness and Integrity Services Ltd, Dublin, Ireland).
Results Treatment of the high-dose group The 100 patients in the HD group had an age of 56.1 ± 13.8 years, 48 were male, 52 female. They were
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treated with XeominÒ 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. Figure 1 shows the histogram of XeominÒ doses applied. 40 patients received XeominÒ exclusively. 36 were pre-treated with BotoxÒ, 24 with DysportÒ. Altogether 54 different muscles were used as target muscles. In dystonia patients the number of target muscles was 46, in spasticity it was 35. Target muscles were localised in the neck (dystonia 8, spasticity 1), the head (dystonia 10, spasticity 3), the shoulder (dystonia 7, spasticity 4), the arm (dystonia 13, spasticity 16), the leg (dystonia 7, spasticity 11) and the trunk (dystonia 2, spasticity 0). Forty-six patients suffered from dystonia. Their age was 56.0 ± 12.9 years, 15 were male, 31 female. They were treated with XeominÒ 519.6 ± 120.8 (min 400, max 1,010) MU. The number of target muscles used per patient was 10.0 ± 3.4 (min 5, max 20). The XeominÒ dose per target muscle was 56.4 ± 19.1 MU. Fifty-four patients suffered from spasticity. Their age was 56.1 ± 14.7 years. 33 were male, 21 female. They were treated with XeominÒ 612.6 ± 176.5 (min 400, max 1,200) MU. 15 suffered from hemispasticity, 13 from arm spasticity, 12 from tetraspasticity, 9 from paraspasticity and 5 from leg spasticity. The number of target muscles used per patient was 6.5 ± 3.2 (min 2, max 19). The XeominÒ dose per target muscle was 114.9 ± 67.1MU.
Table 1 Systemic toxicity questionnaire (STQ) Item
HD group (100 patients) [% of HD group]
RD group (30 patients) [% of RD group]
Remarks
Blurred vision on reading?
6
6
All due to presbyopia
Double vision? Especially on extreme positions?
0
0
Increased sensitivity to bright light? Generalised muscular weakness
0 12
0 0
Shortness of breath
0
0
Fatigue
0
0
Being bedridden
4
0
Diarrhoea
0
0
Constipation
9
0
Dryness of mouth
0
0
Dryness of eyes
0
6
Soor
0
0
Dysphagia
8
6
Pollakisuria
0
0
Feeling of residual urine
10
0
Heart burn
0
0
All due to tetraparesis
All due to tetraparesis All due to tetraparesis All due to local BT effect All due to local BT effect All due to tetraparesis/paraparesis
For all items it was documented whether the phenomenon occurred, whether it could be explained by an underlying condition or by a local botulinum toxin adverse effect and whether its occurrence was compatible with the time course of the botulinum toxin action
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Treatment of the regular-dose group The 30 patients in the RD group had an age of 61.1 ± 9.6 years, 14 were male, 16 female. 27 of them suffered from dystonia, 3 from spasticity. They were treated with XeominÒ 153.2 ± 43.1 (min 60, max 200) MU during 11.8 ± 11.8 (min 4, max 63) injection series. Figure 1 shows a histogram of the XeominÒ doses applied. 3 patients were pre-treated with BotoxÒ, 5 with DysportÒ. Systemic Toxicity Questionnaire Table 1 shows the frequency of positive responses on the STQ for the HD group and for the RD group. The 100 patients in the HD group reported 49 occurrences of an STQ item. 12 of the occurrences were from the 46 patients with dystonia and 38 from the 54 patients with spasticity. The patients in the HD group most frequently reported generalised weakness (12 %). It only occurred in patients with tetraparesis, could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to the underlying condition. The second most frequently reported item was feeling of residual urine (10 %). It only occurred in the patients with tetraparesis or paraparesis, could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to the underlying condition. The third most frequently reported item was constipation (9 %). It only occurred in patients with tetraparesis or paraparesis, could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to the underlying condition. They fourth most frequently reported item was dysphagia (8 %). It only occurred in patients with cervical dystonia receiving nuchal BT therapy. It could not be explained by an underlying condition and followed the time course of BT action. It was considered a local BT adverse effect. The fifth most frequently reported item was blurred vision (6 %). It could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to presbyopia. The sixth most frequently reported item was being bedridden (4 %). It was only seen in patients with tetraparesis. It could not be explained by a local BT effect and did not follow the time course of BT action. It was attributed to the underlying condition. The 30 patients from the RD group reported 9 occurrences of an STQ item. Ten percent each concerned blurred vision, dryness of eye and dysphagia. Blurred vision could not be explained by a local BT effect and did not follow the time course of BT action. It was attributed to presbyopia. Dryness of eye and dysphagia only occurred in patients with blepharospasm and cervical dystonia receiving periocular and nuchal BT injections. It could not be explained
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Fig. 1 Histogram of the XeominÒ doses applied in the study. a Regular-dose group. b High-dose group. c Patients with spasticity in the high-dose group. d Patients with dystonia in the high-dose group
by an underlying condition and followed the time course of BT action. It was considered a local BT effect. Neurological examination NE did not reveal any paresis or any autonomic dysfunction distant from the target muscles which could be attributed to BT therapy. Laboratory screening The results of the laboratory screening are shown in Table 2. Results of the serum chemistry were pathological in the HD group and the RD group in the following descending order: creatinine (10, 6 %), calcium (7, 12 %), chloride (7, 6 %), potassium (7, 0 %), myoglobin (0, 6 %), C-reactive protein (0, 6 %) and urea (3, 6 %). Serum enzymes were pathological in the HD group and in the RD
Safety aspects of incobotulinumtoxinA high-dose therapy
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Table 2 Results of the laboratory investigations Parameter
HD group (n = 30) [%]
RD group (n = 16) [%]
Chemistry Serum chloride
7
6
Serum potassium Serum calcium
7 7
0 12
Serum myoglobin
0
6
Serum C-reactive protein
0
6
10
6
3
0
Serum creatine kinase/MB
90
100
Serum creatine kinase
33
38
Serum aspartate transaminase
27
31
Serum alanine transaminase
15
6
0
6
Serum gamma glutamyl transferase
15
25
Serum lactate dehydrogenase
50
63
Erythrocytes Lymphocytes
7 0
6 0
Granulocytes
0
0
Neutrophils
0
0
Eosinophils
0
0
Basophils
0
0
Platelets
0
0
Serum creatinine Serum urea Enzymes
Serum lipase
Differential blood count
Number of patients with pathological findings given in percent of HD group or RD group
group in the following descending order: creatine kinase/ MB (90, 100 %), lactase dehydrogenase (50, 63 %), creatine kinase (33, 38 %), aspartate transaminase (27, 31 %), gamma glutamyl transferase (15, 21 %), alanine transaminase (15, 31 %) and lipase (0, 6 %). Results of the differential blood count were pathological in the HD group and in the RD group for erythrocytes (7, 6 %). Complete secondary therapy failure None of the patients in the HD group and none of the patients in the RD group showed signs of CSTF.
Discussion Ever since BT is therapeutic potential was first considered by Alan B. Scott (1980) systemic toxicity had to be addressed given the compound’s notorious history as a food poison and a biological weapon. It was Dr. Scott’s great
achievement to demonstrate that BT can produce well controllable and fully reversible paresis of target muscles. Based upon animal models and his careful observation of patients receiving low doses of BT, he was also confident about the compound’s systemic safety. Some years later it was demonstrated by single-fibre electromyography that neuromuscular transmission was temporally abnormal in muscles distant from the target muscles (Lange et al. 1987, Olney et al. 1988, Girlanda et al. 1992). However, these findings were not related to any clinical dysfunction. Although we previously pointed out that systemic BT toxicity clearly is a quantitative problem and as such not necessarily fatal (Dressler 2005), fear of systemic toxicity is still the most vigorous concern against application of increased BT doses. With altogether 100 patients included in the HD group and with an observation period of 10.3 ± 7.0 injection series, this is the largest and most comprehensive study in patients receiving BT high-dose therapy with XeominÒ C400 MU. In the HD group patients received XeominÒ 569.0 ± 159.3 MU. The maximal total dose was XeominÒ 1200 MU. In the STQ several items occurred in the HD group and in the RD group: Generalised weakness, residual urine, constipation, dysphagia, blurred vision, being bedridden, dryness of eyes and dysphagia. In none of the patients the reported items could be attributed to a systemic BT effect. Generalised weakness, being bedridden, residual urine and blurred vision were caused by underlying conditions (tetraparesis, paraparesis, presbyopia). They could not be explained by local BT adverse effects and their time course did not reflect the time course of BT action. Dryness of eyes and dysphagia could not be attributed to underlying conditions. They were attributed to local BT adverse effects. Their time course followed the time course of BT action. Different frequencies of occurrence in dystonia and spasticity patients in the HD group and in the RD group reflect the different distributions of underlying conditions and localisations of BT use. In summary, none of the patients in the HD group or in the RD group showed signs of motor or autonomic dysfunction distant from the target muscles and attributable to the XeominÒ application. LS did not show any remarkable abnormalities for serum chemistry. For serum enzymes creatinine kinase/ MB, creatinine and lactate dehydrogenase were uniformly elevated in the HD group and in the RD group indicating muscle cell damage. Since the serum was obtained after the BT injections were performed, we assume an iatrogenic artefact. For full blood count no remarkable abnormalities were detected. In summary, none of the patients in the HD group and in the RD group showed any abnormalities indicating BT adverse effects. NE neither demonstrated motor nor autonomic systemic adverse effects of BT.
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With the absence of systemic toxicity XeominÒ can therefore be used safely in much higher doses than previously thought. With no indication of looming systemic toxicity produced by the doses used in this study, the threshold for systemic toxicity cannot be determined yet. As pointed out by the US Food and Drugs Administration BT drugs are biologics and as such cannot directly be compared with each other. Data presented here for XeominÒ, therefore, cannot directly be used for the assessment of BotoxÒ. Even less so can they be used for the assessment of DysportÒ where conversion ratios to XeominÒ and BotoxÒ are still a matter of debate. By no means can they be used for predictions about drugs using other BT types, such as rimabotulinumtoxinB (NeuroblocÒ/MyoblocÒ) based on BT type B. For further investigations into BT high-dose therapy several points seem noteworthy: Assuming that BT primarily binds to glycoprotein structures on the nerve terminals within the target muscle the binding capacity of these glycoproteins, i.e. the BT dose per target muscle, should be a much more relevant parameter for evaluation of systemic toxicity than the total BT dose applied to the whole body. Also, based upon this acceptor model, the risk of systemic toxicity should not be linearly related to the BT dose, but should follow a threshold model. Thus, exploring successively higher BT doses should be performed with caution. Additionally, the acceptor density in different target muscles should be a relevant parameter to evaluate systemic toxicity. Unfortunately, this parameter has not been explored yet. Lastly, all data in the present study are based on a BT reconstitution with 2.5 ml 0.9 % NaCl/H2O. Higher dilutions of XeominÒ may produce more systemic BT spread. Another concern against application of higher BT doses has been the formation of BT antibodies. Since the early 1990s, it became clear that the risk of BT antibody formation is directly related to the single dose and inversely related to the inter-injection interval (Dressler and Dirnberger 2000). Therefore, formation of BT antibodies has been a major concern with BT high-dose therapy. However, none of our patients developed antibody-induced CSTF during the observation period. This observation indicates that the single dose is less relevant as a risk factor than previously thought. Observation of antibody-induced CSTF in patients either receiving extremely low single doses or receiving BT therapy with extremely long interinjection intervals already relativized the importance of the these established risk factors (Dressler 2004a; Dressler et al. 2011). According to the study design applied, patients could have developed antibody-induced CSTF during the first 4 injection series, i.e. before they met inclusion criteria. However, as part of another study we did not see antibody-induced CSTF in any of our patients receiving solely XeominÒ since this drug became available in 2005.
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After we previously pointed out that BT drug antigenicity depends on the BT type used, the specific biological activity of the particular BT drug and possibly also of the presence of complexing antibodies (Dressler 2012), lack of BT antibody formation seen in our study using XeominÒ cannot automatically be assumed for other BT type A drugs and certainly not for the only available BT type B drug NeuroblocÒ/MyoBlocÒ. Patients in the HD group received XeominÒ in 8.1 ± 3.7 target muscle. This indicates that XeominÒ highdose therapy allows treatment of more widespread dystonias and spasticities than before. With 88.0 ± 58.6 MU per target muscle the XeominÒ high-dose therapy presented here uses BT doses per target muscle which are comparable to currently recommended doses confirming that the concept of XeominÒ high-dose therapy is not based on excessive dosing per target muscle. Patients treated for dystonia were injected in 10.1 ± 3.4 target muscles. Patients treated for spasticity received injections in 6.5 ± 3.1 target muscles. This indicates a more complex injection scheme in dystonia patients than in spasticity patients. Together with 114.3 ± 66.60 MU per target muscle in spasticity compared 55.7 ± 18.9 MU per target muscle, this reflects the predominant involvement of larger limb muscles in spasticity. XeominÒ can be used in doses of more than 400 MU without detectable systemic toxicity. This allows injection of more target muscles and—where necessary—also of higher XeominÒ doses per target muscle. With this XeominÒ highdose therapy can expand the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies—carefully designed and rigorously monitored—are necessary to explore the threshold dose for clinically detectable systemic toxicity. Acknowledgments The help of F. Francis, MD; K. Escher, MD; P. Tacik, MD and Mrs H Gorzolla with patient and data management is greatly appreciated.
References Aurora SK, Winner P, Freeman MC, Spierings EL, Heiring JO, DeGryse RE, VanDenburgh AM, Nolan ME, Turkel CC (2011) OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56-week PREEMPT clinical program. Headache 51:1358–1573 Bocouture: Summary of Product Characteristics (2013). www. medicines.org.uk/emc/medicine/23251 BotoxÒ: Summary of Product Characteristics (2013). www.medi cines.org.uk/emc/medicine/112 Dressler D (2004a) Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord Suppl 8:S92–S100 Dressler D (2004b) New formulation of BOTOXÒ: complete antibodyinduced therapy failure in hemifacial spasm. J Neurol 251:360
Safety aspects of incobotulinumtoxinA high-dose therapy Dressler D (2005) Botulism caused by consumption of smoked salmon. Nervenarzt 76:763–766 Dressler D (2012) Clinical applications of botulinum toxin. Curr Opin Microbiol 15:325–336 Dressler D, Benecke R (2003) Autonomic side effects of botulinum toxin type B treatment of cervical dystonia and hyperhidrosis. Eur Neurol 49:34–38 Dressler D, Dirnberger G (2000) Botulinum toxin therapy: risk factors for therapy failure. Mov Disord 15(suppl 2):51 Dressler D, Wohlfahrt K, Meyer-Rogge E, Wiest L, Bigalke H (2011) Antibody-induced botulinum toxin therapy failure in dermal indications. Dermatol Surg 36(Suppl 4):2182–2187 Girlanda P, Vita G, Nicolosi C, Milone S, Messina (1992) Botulinum toxin therapy: distant effects on neuromuscular transmission and autonomic nervous system. J Neurol Neurosurg Psychiatry 55:844–845 Go¨schel H, Wohlfarth K, Frevert J, Dengler R, Bigalke H (1997) Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies–therapeutic consequences. Exp Neurol 147:96–102
333 Lange DJ, Brin MF, Warner CL, Fahn S, Lovelace R (1987) Distant effects of local injection of botulinum toxin. Muscle Nerve 10:552–555 Olney RK, Aminoff MJ, Gelb DJ, Lowenstein DH (1988) Neuromuscular effects distant from the site of botulinum neurotoxin injection. Neurology 38:1780–1783 Rosow DE, Parikh P, Vivero RJ, Casiano RR, Lundy DS (2013) Considerations for initial dosing of botulinum toxin in treatment of adductor spasmodic dysphonia. Otolaryngol Head Neck Surg 148:1003–1006 Scott AB (1980) Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J Pediatr Ophthalmol Strabismus 17:21–25 Truong D, Dressler D, Hallett M (2009) Manual of botulinum toxin therapy. Cambridge University Press, Cambridge Vistabel: Summary of Product Characteristics (2013). www.medi cines.org.uk/emc/medicine/17580 XeominÒ: Summary of Product Characteristics (2013). www. medicines.org.uk/emc/medicine/20666
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PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE
Safety aspects of incobotulinumtoxinA high-dose therapy Dirk Dressler • Fereshte Adib Saberi Katja Kollewe • Christoph Schrader
•
Received: 28 February 2014 / Accepted: 25 May 2014 / Published online: 17 July 2014 Ó Springer-Verlag Wien 2014
Abstract Botulinum toxin (BT) used for dystonia and spasticity is dosed according to the number of target muscles and the severity of their muscle hyperactivities. With this no other drug is used in a broader dose range than BT. The upper end of this range, however, still needs to be explored. We wanted to do this by a prospective noninterventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (XeominÒ) high-dose therapy (HD group, n = 100, single dose C400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose B200 MU). At the measurement point all patients were evaluated for systemic BT toxicity, i.e. systemic motor impairment or systemic autonomic dysfunction. HD group patients (56.1 ± 13.8 years, 46 dystonia, 54 spasticity) were treated with XeominÒ 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. In dystonia patients the number of target muscles was 46 and the dose per target muscle 56.4 ± 19.1 MU, in spasticity patients 35 and 114.9 ± 67.1 MU. HD and RD group patients reported 58 occurrences of items on the systemic toxicity questionnaire. Generalised weakness, being bedridden, feeling of residual urine and constipation were caused by the underlying tetra- or paraparesis, blurred vision by presbyopia. Dysphagia and dryness of eye were local BT adverse effects. Neurologic examination, serum chemistry and full blood count did not indicate any systemic adverse effects. Elevated serum levels for creatine kinase/MB, creatine
D. Dressler (&) F. Adib Saberi K. Kollewe C. Schrader Movement Disorders Section, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany e-mail: [email protected]
kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibodyinduced therapy failure. XeominÒ can be used safely in doses C400 MU and up to 1,200 MU without detectable systemic toxicity. This allows expanding the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies—carefully designed and rigorously monitored—are necessary to explore the threshold dose for clinically detectable systemic toxicity. Keywords Botulinum toxin Therapeutic use Highdose therapy Safety Systemic toxicity Antibody formation
Introduction Over the last 30 years botulinum toxin (BT) has gained widespread use for the treatment of numerous medical conditions caused by overactive muscles or overactive exocrine glands (Truong et al. 2009). Its use for treatment of non-motor pain is currently investigated (Aurora et al. 2011). No other drug is used in a broader range dose. In registered indications recommended single doses start from 20 MU of onabotulinumtoxinA (BotoxÒ, VistabelÒ, Botox CosmeticÒ) (VistabelÒ: Summary of Product Characteristics 2013) or 20 MU of incobotulinumtoxinA (XeominÒ, BocoutureÒ) (BocoutureÒ: Summary of Product Characteristics 2013) for glabella lines to BotoxÒ 300 MU for cervical dystonia (BotoxÒ: Summary of Product Characteristics 2013) or XeominÒ 400 MU for arm spasticity after stroke (XeominÒ: Summary of Product Characteristics 2013). Under off-label use conditions even lower single
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doses of BotoxÒ 1.25 MU (Rosow et al. 2013) have been used for spasmodic dysphonia. The upper end of the therapeutic dose range, however, still needs to be explored. Maximal recommended single doses of around BotoxÒ 400 MU or XeominÒ 400 MU allow to inject only a limited number of target muscles thus preventing exploiting the full potential of BT therapy. Since current dose recommendations are not based on any negative safety data, we felt encouraged to gradually increase the maximal single doses in our clinical practice over the last years under careful monitoring of systemic toxicity and the occurrence of antibody-induced complete secondary therapy failure (CSTF). This study summarises our experience with the safety of XeominÒ high-dose therapy.
(5) body weight C50 kg. Exclusion criteria: (1) inability to cooperate; (2) conditions affecting the normal neuromuscular junction functioning; (3) Conditions potentially able to produce fatigue such as multiple sclerosis or cancer. (4) drugs affecting the autonomic nervous system such as anticholinergics; (5) peripherally acting antispastic drugs such as dantrolene; (6) continuous intrathecal baclofen pumps. Other oral antispastic drugs were allowed when doses were stable for at least 6 months prior to the measurement point. Anticoagulation was allowed, but recent INR values had to be provided. For the RD group 30 patients fulfilling identical inclusion and exclusion criteria as patients in the HD group were randomly selected. The only difference was that their single dose was XeominÒ B200 MU.
Methods
Botulinum toxin drugs
Definitions
All patients were treated with XeominÒ at the measurement point and for the previous two injection series. Before this, BotoxÒ and abobotulinumtoxinA (DysportÒ) may have been applied. XeominÒ was reconstituted with 2.5 ml 0.9 % NaCl/H2O.
Single dose is the amount of BT given at each injection series. Injection series is the application of BT on one given day. Measurement point is the time when the patient is evaluated by STQ. Observation period is the time from the first BT application in our clinics to the measurement point. Inter-injection interval is the time between two subsequent injection series. Target muscle is a muscle receiving BT. Treatment cycle is the BT application with the subsequent time period until the next injection series. Design The study followed a prospective non-interventional design comparing the study group receiving XeominÒ high-dose therapy (HD group) to a control group receiving XeominÒ regular-dose therapy (RD group). At the measurement point all patients in the HD group and in the RD group were evaluated for the study parameter, i.e. systemic toxicity manifesting as dysfunction of the motor system and the autonomic nervous system distant from the injection site. Additional study parameter was the occurrence of CSTF. All findings in the HD group were compared to those in the RD group. Patients All patients were recruited from our BT outpatient clinics. Treatment data of all patients receiving BT treatment are stored in a digital data base. For the HD group 100 patients fulfilling the following inclusion and exclusion criteria were randomly selected. Inclusion criteria: (1) single dose CXeominÒ 400 MU; (2) number of injection series C4; (3) various forms of dystonia or spasticity; (4) age C 18 years;
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Botulinum toxin therapy XeominÒ was dosed according to the individual symptomatology and dose modifiers in an algorithm developed by us over the last 25 years. All XeominÒ dose C500 MU were titrated over several subsequent injection series. Interinjection intervals were generally set to 12 weeks. If necessary, shortened inter-injection intervals could be used. The minimum inter-injection interval allowed was 10 weeks. XeominÒ was applied clinically. Where necessary, ultrasound guidance or electromyographic guidance (including electrostimulation) was used. XeominÒ doses for each target muscle were distributed to several injection sites, so that the volume per injection site was around 0.5 ml. Evaluation Systemic toxicity was evaluated by STQ, NE and LS. The STQ was developed based on our previous observations on the systemic toxicity of BT type B (Dressler and Benecke 2003). Details are shown in Table 1 (see ‘‘Results’’). Patients were asked whether any of the items occurred during the last two injection series. It was also documented whether the occurrence could be explained by an underlying condition or a local BT adverse effect and whether it was compatible with the time course of the BT action. NE tested the BT effect on the target muscle. It also included examination of muscle strength on acute maximal activation and muscle fatigue on repeated activations in selected
Safety aspects of incobotulinumtoxinA high-dose therapy
muscles distant from the target muscles. Additionally, cranial nerve function including pupillomotor function and double vision, as well as the moisture of skin, oral mucosa and eyes were tested. LS were performed when the patient received BT re-injections. It included chemistry, enzymes and full blood count. Details are shown in Table 2 (see ‘‘Results’’). CSTF was evaluated by the criteria previously described by us (Dressler 2004a, b). They include initially sufficient BT effects, subsequently shortened durations of action and complete lack of BT efficacy on three subsequent BT injection series. If there was CSTF, BT antibody titres were studied using the mouse hemidiaphragm assay (Go¨schel et al. 1997) provided by Toxogen, Hannover, Germany. Randomisation Randomisation was performed by random.org (Randomness and Integrity Services Ltd, Dublin, Ireland).
Results Treatment of the high-dose group The 100 patients in the HD group had an age of 56.1 ± 13.8 years, 48 were male, 52 female. They were
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treated with XeominÒ 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. Figure 1 shows the histogram of XeominÒ doses applied. 40 patients received XeominÒ exclusively. 36 were pre-treated with BotoxÒ, 24 with DysportÒ. Altogether 54 different muscles were used as target muscles. In dystonia patients the number of target muscles was 46, in spasticity it was 35. Target muscles were localised in the neck (dystonia 8, spasticity 1), the head (dystonia 10, spasticity 3), the shoulder (dystonia 7, spasticity 4), the arm (dystonia 13, spasticity 16), the leg (dystonia 7, spasticity 11) and the trunk (dystonia 2, spasticity 0). Forty-six patients suffered from dystonia. Their age was 56.0 ± 12.9 years, 15 were male, 31 female. They were treated with XeominÒ 519.6 ± 120.8 (min 400, max 1,010) MU. The number of target muscles used per patient was 10.0 ± 3.4 (min 5, max 20). The XeominÒ dose per target muscle was 56.4 ± 19.1 MU. Fifty-four patients suffered from spasticity. Their age was 56.1 ± 14.7 years. 33 were male, 21 female. They were treated with XeominÒ 612.6 ± 176.5 (min 400, max 1,200) MU. 15 suffered from hemispasticity, 13 from arm spasticity, 12 from tetraspasticity, 9 from paraspasticity and 5 from leg spasticity. The number of target muscles used per patient was 6.5 ± 3.2 (min 2, max 19). The XeominÒ dose per target muscle was 114.9 ± 67.1MU.
Table 1 Systemic toxicity questionnaire (STQ) Item
HD group (100 patients) [% of HD group]
RD group (30 patients) [% of RD group]
Remarks
Blurred vision on reading?
6
6
All due to presbyopia
Double vision? Especially on extreme positions?
0
0
Increased sensitivity to bright light? Generalised muscular weakness
0 12
0 0
Shortness of breath
0
0
Fatigue
0
0
Being bedridden
4
0
Diarrhoea
0
0
Constipation
9
0
Dryness of mouth
0
0
Dryness of eyes
0
6
Soor
0
0
Dysphagia
8
6
Pollakisuria
0
0
Feeling of residual urine
10
0
Heart burn
0
0
All due to tetraparesis
All due to tetraparesis All due to tetraparesis All due to local BT effect All due to local BT effect All due to tetraparesis/paraparesis
For all items it was documented whether the phenomenon occurred, whether it could be explained by an underlying condition or by a local botulinum toxin adverse effect and whether its occurrence was compatible with the time course of the botulinum toxin action
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Treatment of the regular-dose group The 30 patients in the RD group had an age of 61.1 ± 9.6 years, 14 were male, 16 female. 27 of them suffered from dystonia, 3 from spasticity. They were treated with XeominÒ 153.2 ± 43.1 (min 60, max 200) MU during 11.8 ± 11.8 (min 4, max 63) injection series. Figure 1 shows a histogram of the XeominÒ doses applied. 3 patients were pre-treated with BotoxÒ, 5 with DysportÒ. Systemic Toxicity Questionnaire Table 1 shows the frequency of positive responses on the STQ for the HD group and for the RD group. The 100 patients in the HD group reported 49 occurrences of an STQ item. 12 of the occurrences were from the 46 patients with dystonia and 38 from the 54 patients with spasticity. The patients in the HD group most frequently reported generalised weakness (12 %). It only occurred in patients with tetraparesis, could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to the underlying condition. The second most frequently reported item was feeling of residual urine (10 %). It only occurred in the patients with tetraparesis or paraparesis, could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to the underlying condition. The third most frequently reported item was constipation (9 %). It only occurred in patients with tetraparesis or paraparesis, could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to the underlying condition. They fourth most frequently reported item was dysphagia (8 %). It only occurred in patients with cervical dystonia receiving nuchal BT therapy. It could not be explained by an underlying condition and followed the time course of BT action. It was considered a local BT adverse effect. The fifth most frequently reported item was blurred vision (6 %). It could not be explained by a local BT adverse effect and did not follow the time course of BT action. It was attributed to presbyopia. The sixth most frequently reported item was being bedridden (4 %). It was only seen in patients with tetraparesis. It could not be explained by a local BT effect and did not follow the time course of BT action. It was attributed to the underlying condition. The 30 patients from the RD group reported 9 occurrences of an STQ item. Ten percent each concerned blurred vision, dryness of eye and dysphagia. Blurred vision could not be explained by a local BT effect and did not follow the time course of BT action. It was attributed to presbyopia. Dryness of eye and dysphagia only occurred in patients with blepharospasm and cervical dystonia receiving periocular and nuchal BT injections. It could not be explained
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Fig. 1 Histogram of the XeominÒ doses applied in the study. a Regular-dose group. b High-dose group. c Patients with spasticity in the high-dose group. d Patients with dystonia in the high-dose group
by an underlying condition and followed the time course of BT action. It was considered a local BT effect. Neurological examination NE did not reveal any paresis or any autonomic dysfunction distant from the target muscles which could be attributed to BT therapy. Laboratory screening The results of the laboratory screening are shown in Table 2. Results of the serum chemistry were pathological in the HD group and the RD group in the following descending order: creatinine (10, 6 %), calcium (7, 12 %), chloride (7, 6 %), potassium (7, 0 %), myoglobin (0, 6 %), C-reactive protein (0, 6 %) and urea (3, 6 %). Serum enzymes were pathological in the HD group and in the RD
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Table 2 Results of the laboratory investigations Parameter
HD group (n = 30) [%]
RD group (n = 16) [%]
Chemistry Serum chloride
7
6
Serum potassium Serum calcium
7 7
0 12
Serum myoglobin
0
6
Serum C-reactive protein
0
6
10
6
3
0
Serum creatine kinase/MB
90
100
Serum creatine kinase
33
38
Serum aspartate transaminase
27
31
Serum alanine transaminase
15
6
0
6
Serum gamma glutamyl transferase
15
25
Serum lactate dehydrogenase
50
63
Erythrocytes Lymphocytes
7 0
6 0
Granulocytes
0
0
Neutrophils
0
0
Eosinophils
0
0
Basophils
0
0
Platelets
0
0
Serum creatinine Serum urea Enzymes
Serum lipase
Differential blood count
Number of patients with pathological findings given in percent of HD group or RD group
group in the following descending order: creatine kinase/ MB (90, 100 %), lactase dehydrogenase (50, 63 %), creatine kinase (33, 38 %), aspartate transaminase (27, 31 %), gamma glutamyl transferase (15, 21 %), alanine transaminase (15, 31 %) and lipase (0, 6 %). Results of the differential blood count were pathological in the HD group and in the RD group for erythrocytes (7, 6 %). Complete secondary therapy failure None of the patients in the HD group and none of the patients in the RD group showed signs of CSTF.
Discussion Ever since BT is therapeutic potential was first considered by Alan B. Scott (1980) systemic toxicity had to be addressed given the compound’s notorious history as a food poison and a biological weapon. It was Dr. Scott’s great
achievement to demonstrate that BT can produce well controllable and fully reversible paresis of target muscles. Based upon animal models and his careful observation of patients receiving low doses of BT, he was also confident about the compound’s systemic safety. Some years later it was demonstrated by single-fibre electromyography that neuromuscular transmission was temporally abnormal in muscles distant from the target muscles (Lange et al. 1987, Olney et al. 1988, Girlanda et al. 1992). However, these findings were not related to any clinical dysfunction. Although we previously pointed out that systemic BT toxicity clearly is a quantitative problem and as such not necessarily fatal (Dressler 2005), fear of systemic toxicity is still the most vigorous concern against application of increased BT doses. With altogether 100 patients included in the HD group and with an observation period of 10.3 ± 7.0 injection series, this is the largest and most comprehensive study in patients receiving BT high-dose therapy with XeominÒ C400 MU. In the HD group patients received XeominÒ 569.0 ± 159.3 MU. The maximal total dose was XeominÒ 1200 MU. In the STQ several items occurred in the HD group and in the RD group: Generalised weakness, residual urine, constipation, dysphagia, blurred vision, being bedridden, dryness of eyes and dysphagia. In none of the patients the reported items could be attributed to a systemic BT effect. Generalised weakness, being bedridden, residual urine and blurred vision were caused by underlying conditions (tetraparesis, paraparesis, presbyopia). They could not be explained by local BT adverse effects and their time course did not reflect the time course of BT action. Dryness of eyes and dysphagia could not be attributed to underlying conditions. They were attributed to local BT adverse effects. Their time course followed the time course of BT action. Different frequencies of occurrence in dystonia and spasticity patients in the HD group and in the RD group reflect the different distributions of underlying conditions and localisations of BT use. In summary, none of the patients in the HD group or in the RD group showed signs of motor or autonomic dysfunction distant from the target muscles and attributable to the XeominÒ application. LS did not show any remarkable abnormalities for serum chemistry. For serum enzymes creatinine kinase/ MB, creatinine and lactate dehydrogenase were uniformly elevated in the HD group and in the RD group indicating muscle cell damage. Since the serum was obtained after the BT injections were performed, we assume an iatrogenic artefact. For full blood count no remarkable abnormalities were detected. In summary, none of the patients in the HD group and in the RD group showed any abnormalities indicating BT adverse effects. NE neither demonstrated motor nor autonomic systemic adverse effects of BT.
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With the absence of systemic toxicity XeominÒ can therefore be used safely in much higher doses than previously thought. With no indication of looming systemic toxicity produced by the doses used in this study, the threshold for systemic toxicity cannot be determined yet. As pointed out by the US Food and Drugs Administration BT drugs are biologics and as such cannot directly be compared with each other. Data presented here for XeominÒ, therefore, cannot directly be used for the assessment of BotoxÒ. Even less so can they be used for the assessment of DysportÒ where conversion ratios to XeominÒ and BotoxÒ are still a matter of debate. By no means can they be used for predictions about drugs using other BT types, such as rimabotulinumtoxinB (NeuroblocÒ/MyoblocÒ) based on BT type B. For further investigations into BT high-dose therapy several points seem noteworthy: Assuming that BT primarily binds to glycoprotein structures on the nerve terminals within the target muscle the binding capacity of these glycoproteins, i.e. the BT dose per target muscle, should be a much more relevant parameter for evaluation of systemic toxicity than the total BT dose applied to the whole body. Also, based upon this acceptor model, the risk of systemic toxicity should not be linearly related to the BT dose, but should follow a threshold model. Thus, exploring successively higher BT doses should be performed with caution. Additionally, the acceptor density in different target muscles should be a relevant parameter to evaluate systemic toxicity. Unfortunately, this parameter has not been explored yet. Lastly, all data in the present study are based on a BT reconstitution with 2.5 ml 0.9 % NaCl/H2O. Higher dilutions of XeominÒ may produce more systemic BT spread. Another concern against application of higher BT doses has been the formation of BT antibodies. Since the early 1990s, it became clear that the risk of BT antibody formation is directly related to the single dose and inversely related to the inter-injection interval (Dressler and Dirnberger 2000). Therefore, formation of BT antibodies has been a major concern with BT high-dose therapy. However, none of our patients developed antibody-induced CSTF during the observation period. This observation indicates that the single dose is less relevant as a risk factor than previously thought. Observation of antibody-induced CSTF in patients either receiving extremely low single doses or receiving BT therapy with extremely long interinjection intervals already relativized the importance of the these established risk factors (Dressler 2004a; Dressler et al. 2011). According to the study design applied, patients could have developed antibody-induced CSTF during the first 4 injection series, i.e. before they met inclusion criteria. However, as part of another study we did not see antibody-induced CSTF in any of our patients receiving solely XeominÒ since this drug became available in 2005.
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After we previously pointed out that BT drug antigenicity depends on the BT type used, the specific biological activity of the particular BT drug and possibly also of the presence of complexing antibodies (Dressler 2012), lack of BT antibody formation seen in our study using XeominÒ cannot automatically be assumed for other BT type A drugs and certainly not for the only available BT type B drug NeuroblocÒ/MyoBlocÒ. Patients in the HD group received XeominÒ in 8.1 ± 3.7 target muscle. This indicates that XeominÒ highdose therapy allows treatment of more widespread dystonias and spasticities than before. With 88.0 ± 58.6 MU per target muscle the XeominÒ high-dose therapy presented here uses BT doses per target muscle which are comparable to currently recommended doses confirming that the concept of XeominÒ high-dose therapy is not based on excessive dosing per target muscle. Patients treated for dystonia were injected in 10.1 ± 3.4 target muscles. Patients treated for spasticity received injections in 6.5 ± 3.1 target muscles. This indicates a more complex injection scheme in dystonia patients than in spasticity patients. Together with 114.3 ± 66.60 MU per target muscle in spasticity compared 55.7 ± 18.9 MU per target muscle, this reflects the predominant involvement of larger limb muscles in spasticity. XeominÒ can be used in doses of more than 400 MU without detectable systemic toxicity. This allows injection of more target muscles and—where necessary—also of higher XeominÒ doses per target muscle. With this XeominÒ highdose therapy can expand the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies—carefully designed and rigorously monitored—are necessary to explore the threshold dose for clinically detectable systemic toxicity. Acknowledgments The help of F. Francis, MD; K. Escher, MD; P. Tacik, MD and Mrs H Gorzolla with patient and data management is greatly appreciated.
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