Strabismus

Extraocular muscles adjacent to the injection site can be affected, causing ptosis or vertical deviation, especially with higher doses of BOTOX®. The incidence rates of these adverse effects in 2058 adults who received a total of 3650 injections for horizontal strabismus are 15.7% and 16.9%, respectively.4

Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision, or past-pointing. Covering the affected eye may alleviate these symptoms.

The incidence of ptosis was 0.9% after inferior rectus injection and 37.7% after superior rectus injection.

Ptosis (0.3%) and vertical deviation greater than two prism diopters (2.1%) were reported to persist for over six months in a larger series of 5587 injections of horizontal muscles in 3104 patients.

In these patients, the injection procedure itself caused nine scleral perforations. Avitreous hemorrhage occurred in one case and later cleared. No retinal detachment or visual loss occurred in any case. Sixteen retrobulbar hemorrhages occurred without visual loss. Decompression of the orbit after five minutes was done to restore retinal circulation in one case. Five eyes had pupillary change consistent with ciliary ganglion damage (Adie’s pupil).

One patient developed anterior segment ischemia after receiving BOTOX® injection into the medial rectus muscle under direct visualization for esotropia.

Immunogenicity

Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX® treatment by inactivating the biological activity of the toxin. The rate of formation of neutralizing antibodies in patients receiving BOTOX® has not been well studied.

In the phase 3 cervical dystonia study1 that enrolled only patients with a history of receiving BOTOX® for multiple treatment sessions, at study entry there were 192 patients with antibody assay results, of whom 33 (17%) had a positive assay for neutralizing activity. There were 96 patients in the randomized period of the phase 3 study with valid assays at both study entry and end and who were neutralizing activity negative at entry. Of these 96, 2 patients (2%) converted to positive for neutralizing activity. Both of these converting patients were among the 52 who had received two BOTOX® treatments between the two assays; none were in the group randomized to placebo in the controlled comparison period of the study.

In the randomized period of the cervical dystonia study, patients in the BOTOX® group whose baseline assays were neutralizing antibody negative showed improvements on CDSS (n=64, mean CDSS change -2.1) while patients whose baseline assays were neutralizing antibody positive did not (n=14, mean CDSS change +1.1). However, in uncontrolled studies there are also individual patients who are perceived as continuing to respond to treatments despite the presence of neutralizing activity. Not all patients who become non-responsive to BOTOX® after an initial period of clinical response have demonstrable levels of neutralizing activity.

One patient among the 445 hyperhidrosis patients with analyzed specimens showed the presence of neutralizing antibodies.

The data reflect the patients whose test results were considered positive or negative for neutralizing activity to BOTOX® in a mouse protection assay. The results of these tests are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, concomitant medications and underlying disease. For these reasons, comparison of the incidence of neutralizing activity to BOTOX® with the incidence reported to other products may be misleading.

The critical factors for neutralizing antibody formation have not been well characterized. The results from some studies suggest that BOTOX® injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.

DRUG INTERACTIONS
Co-administration of BOTOX® and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated.

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

REFERENCE

7. Data on file, Allergan, Inc. 1999.

8. Data on file, Allergan, Inc. Arandomized, multicenter, double-blind, parallel clinical trial to compare the safety and efficacy of BOTOX® (botulinum toxin type A) purified neurotoxin complex manufactured from neurotoxin complex batch BCB2024 to that manufactured from neurotoxin complex batch 79-11 in blepharospasm patients. 1997.