Incorrect Reconstitution of IncobotulinumtoxinA Leads to Loss of Neurotoxin
June 2014 | Volume 13 | Issue 6 | Original Article | 735 | Copyright © 2014
Wayne D. Carey MD
Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada
BACKGROUND: IncobotulinumtoxinA (INCO) was approved for aesthetic use in the United States in 2011. When reconstituted per manufacturer’s instructions, diminished delivery of INCO in US may result.
OBJECTIVE: Investigators sought to determine whether potential loss of decreased motor activity could be demonstrated, using a simple reconstitution technique.
METHODS and MATERIALS: In this 5-patient study, investigators added 2.0 mL of saline to INCO powder at the bottom of the first of 5 vials, swirling gently to dissolve INCO powder at the bottom. Reconstituted INCO was discarded and the cap was replaced. The “empty” vial then received 0.6 mL of saline, and was swirled and inverted 3 times to ensure dissolution. The 0.6 mL from the first vial was added to the second “empty” vial and the process was repeated for the remaining 3 vials (5 vials per patient). Patients were injected from reconstitution of “empty” vials to determine neuromodulatory activity. Pre- and post-treatment patient photographs of maximal contraction were taken.
RESULTS: Markedly diminished maximal frown could be observed in all 5 patients.
CONCLUSION: Improper reconstitution of INCO, or swirling without inversion of the vial following saline injection, can result in significant loss of units of the neurotoxin in the clinical setting.
J Drugs Dermatol. 2014;13(6):735-738.
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IncobotulinumtoxinA (INCO; Xeomin® in the United States, Canada / “botulinum toxin A free of complexing proteins» or Bocouture® in Europe and other parts of the world) is distributed by Merz Aesthetics Inc. and Merz Pharmaceuticals LLC in Greensboro, NC. INCO has been in approved use in Europe since 2005, with availability in 20 countries and with over 261,000 patients treated.1
Recently, anecdotal reports from North American aesthetic clinicians have suggested some variance in efficacy amongst BoNTAproducts2 despite many studies demonstrating comparable effectiveness of toxins when dosed properly. Studies of more than 2000 patients have shown comparable dosing, efficacy, and safety comparing INCO to onabotulinumtoxinA (ONA; Botox®, Allergan, Irvine, CA).3-15 These anecdotal reports raise the issue of variables, if any, which may be associated with differences in efficacy.
One difference may be related to how INCO is supplied in Europe, compared to North America. In Europe, INCO appears as a compressed “puck” at the bottom of its vial. In North America, INCO may appear as a puck with most of the neuromodulator at the bottom of the vial. However, it is often present as a loose powder, clustered around and inside the rubber cap, as well as on the sides of the vial, possibly due to product shifting during overseas transport (Figure 1).2 We wondered whether physical differences in INCO presentation in its vial would influence reconstitution technique, and thus account for the anecdotal comments upon differences in efficacy.
Our hypothesis is that, because INCO can be found distributed throughout the vial rather than solely at the bottom of the vial, failure to invert a vial of INCO during the addition of saline results in reconstitution of less than 100 percent of the available neuromodulator, possibly resulting in diminished efficacy upon injection.
The idea of incomplete reconstitution arose from an inadvertent swirl and inversion of vials of INCO by the author, rather than the usual simple swirl reconstitution technique as traditionally used for ONA. The author typically uses a 2 cc dilution of INCO or ONA. This technique came about when we noticed that there was no foaming of the ONA solution when saline was injected into the inverted vial. This technique was continued when we started reusing INCO. When injected into the patient, the INCO reconstituted from a swirled and inverted vials resulted in a clinically equivalent effectiveness of neuromuscular paralysis as compared with ONA injections in our practice. This serendipitous inversion led us to design an experiment to determine if, by simply altering the reconstitution technique of INCO, optimization of the clinical effect of decreased motor activity could be demonstrated.
Materials and Methods
Five patients who were naïve to BoNTA injections were selected for this trial. Vials of INCO were included in the study only if there was visible powder around and inside the vial cap. Vials that contained INCO in complete or slightly disrupted puck form were not included in the study (Figure 1).Reconstitution Method
Step 1. Five vials of INCO were each reconstituted with 2.0 mL of sterile, preserved 0.9% sodium chloride (saline). The vials were