Xeomin (Page 8 of 12)

12.3 Pharmacokinetics

Using currently available analytical technology, it is not possible to detect XEOMIN in the peripheral blood following intramuscular or intraglandular injection at the recommended doses.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies to evaluate the carcinogenic potential of XEOMIN have not been conducted.

Mutagenesis

Genotoxicity studies have not been conducted for XEOMIN.

Impairment of Fertility

In a fertility and early embryonic development study in rabbits, males and females were dosed with XEOMIN (1.25 Units/kg, 2.5 Units/kg, or 3.5 Units/kg) intramuscularly every two weeks for 5 and 3 doses, respectively, beginning 2 weeks prior to mating. No effects on mating or fertility were observed. The highest dose tested is approximately twice the maximum recommended human dose for cervical dystonia (120 Units) on a body weight basis.

14 CLINICAL STUDIES

14.1 Chronic Sialorrhea

Chronic Sialorrhea in Adult Patients

The efficacy and safety of XEOMIN for the treatment of chronic sialorrhea in adult patients were evaluated in a double-blind, placebo-controlled clinical trial that enrolled a total of 184 patients with chronic sialorrhea resulting from Parkinson’s disease, atypical parkinsonism, stroke, or traumatic brain injury, that was present for at least three months. Patients with a history of aspiration pneumonia, amyotrophic lateral sclerosis, salivary gland or duct malformation, and gastroesophageal reflux disease were excluded. The study consisted of a 16-week main phase, followed by an extension period of dose-blinded treatment with XEOMIN.

In the main phase, a fixed total dose of XEOMIN (100 Units or 75 Units) or placebo was administered into the parotid and submandibular salivary glands in a 3:2 dose ratio. The co-primary efficacy variables were the change in unstimulated Salivary Flow Rate (uSFR, Table 14) and the change in Global Impression of Change Scale (GICS, Table 15) at Week 4 post-injection. A total of 173 treated patients completed the main phase of the study. For both the uSFR and GICS, XEOMIN 100 Units was significantly better than placebo (see Table 14 and Table 15). XEOMIN 75 Units was not significantly better than placebo.

Table 14: Mean Change in uSFR (g/min) from Baseline at Week 4, 8, 12, and 16 of Main Phase
XEOMIN 100 Units Placebo
N=73 N=36
*
p=0.004
Week 4* -0.13 -0.04
Week 8 -0.13 -0.02
Week 12 -0.12 -0.03
Week 16 -0.11 -0.01
Table 15: Mean GICS at Week 4, 8, 12, and 16 of Main Phase
XEOMIN 100 Units Placebo
N=74 N=36
*
p=0.002
Week 4* 1.25 0.67
Week 8 1.30 0.47
Week 12 1.21 0.56
Week 16 0.93 0.41

In the extension period, patients received up to three additional treatments with XEOMIN 100 Units or 75 Units every 16±2 weeks, for a total exposure duration of up to 64 weeks. Patients had periodic dental examinations to monitor for changes in dentition and oral mucosa. A total of 151 patients completed the extension period.

Chronic Sialorrhea in Pediatric Patients

The efficacy and safety of XEOMIN for the treatment of chronic sialorrhea in pediatric patients were evaluated in a prospective, randomized, double-blind, placebo-controlled (ages 6-17 years), parallel-group, multicenter trial that enrolled and treated a total of 216 pediatric patients 6-17 years of age with chronic sialorrhea associated with cerebral palsy, other genetic or congenital disorders, or traumatic brain injury. An additional 35 patients 2-5 years of age were treated with open-label XEOMIN in that study. The study consisted of a 16-week main phase, followed by an open-label extension period of treatment with XEOMIN where patients could receive up to 3 additional treatments with XEOMIN every 16 ± 2 weeks, for a total exposure duration of up to 64 weeks (222 patients completed the extension period).

In the main phase, patients 6-17 years of age were administered a total dose of XEOMIN according to body weight (up to 75 Units), or placebo, into the parotid and submandibular glands in a 3:2 dose ratio, using ultrasound guidance. Patients 2-5 years of age all received open-label treatment with XEOMIN, according to body weight, using ultrasound guidance. Patients with a body weight <12 kg were excluded.

The primary efficacy analysis was conducted in the 6-17 years of age patient group. The co-primary endpoints were the change in unstimulated Salivary Flow Rate (uSFR, Table 16) and carer’s Global Impression of Change Scale (GICS, Table 17) at Week 4 post-injection.

For both the uSFR and GICS, XEOMIN was statistically significantly better than placebo (see Table 16 and Table 17).

Table 16: Mean change in uSFR (g/min) from Baseline at Week 4, 8, 12, and 16 of Main Phase
XEOMIN(6-17 years)N = 148 Placebo(6-17 years)N=72
*
p=0.0012
Week 4* -0.14 -0.07
Week 8 -0.16 -0.07
Week 12 -0.16 -0.06
Week 16 -0.15 -0.08
Table 17: Mean carer’s GICS at Week 4, 8, 12, and 16 of Main Phase
XEOMIN(6-17 years)N = 148 Placebo(6-17 years)N=72
*
p=0.0320
Week 4* 0.91 0.63
Week 8 0.94 0.54
Week 12 0.87 0.47
Week 16 0.77 0.38

Efficacy in pediatric patients 2 to 5 years of age is extrapolated from the finding of efficacy in older pediatric patients.

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