Safety aspects of incobotulinumtoxinA high-dose therapy

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 non-interventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (Xeomin(®)) high-dose therapy (HD group, n = 100, single dose ≥400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose ≤200 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 Xeomin(®) 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 kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibody-induced therapy failure. Xeomin(®) can be used safely in doses ≥400 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.

Clinical differences between botulinum neurotoxin type A and B

“…However, in this series, patients were treated with fixed doses, which were somewhat lower (not exceeding 50U for blepharospasm and 120e240U for CD), than used in clinical practice. In some patients, higher doses are required when CD is complex (Dressler and Saberi, 2006). We do not have data on high doses at shorter intervals over a longer time frame.…”

Employment of higher doses of botulinum toxin type A to reduce spasticity after stroke

“…Excluding other 26 articles not meeting inclusion criteria, we obtained full copies of the 16 potentially suitable reports for further assessment. After inclusion of 2 articles of interest from the reference lists of the selected articles and exclusion of other 10 articles, 8 studies met study eligibility criteria, and were finally included in the overall review [8][9][10]20,[22][23][24][25] (Tables 1 and 2). …”

“…In fact, the mean FAT score improved, but the benefit was not significant [24]. Finally, a recent study demonstrated that very high doses of incobotulinumtoxinA (minimum 400 U and maximum 1200 U) injected into fifty-four patients suffering from spasticity of several etiologies (15 suffered with hemispasticity, 13 with arm spasticity, 12 with tetraspasticity, 9 with paraspasticity, and 5 with leg spasticity) did not cause any paresis or any autonomic dysfunction distant from the target muscles which could be attributed to BoNT therapy or complete secondary therapy failure [25]. Moreover, the few side effects reported (weakness, feeling of residual urine, constipation, being bedridden, especially in tetraparesis or paraparesis, whereas blurred vision attributed to presbyopia) have been attributed to the underlying condition and not to BoNT-A action [22].…”

High doses of incobotulinumtoxinA for the treatment of post-stroke spasticity: are they safe and effective?

“…In a prospective, open-label noninterventional study, Dressler evaluated the safety outcomes in 15 suffered with hemispasticity, 13 with arm spasticity, and 5 with leg spasticity due to stroke for 90% of the patients treated up to 1200 U of incobotulinumtoxinA (dose range: 400-1200 U; mean dose ± standard deviation: 570.1 ± 158.9 U). No signs of motor or autonomic dysfunction have been reported and no patient developed Ab production and secondary treatment failure [13]. The safety of 600 U of incobotulinumtoxinA has been also tested in 11 spastic stroke survivors evaluating possible changes in autonomic heart drive.…”