"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
Mechanism of Action
XEOMIN blocks cholinergic transmission at the neuromuscular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerve endings. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of SNAP25, a presynaptic target protein essential for the release of acetylcholine. Impulse transmission is re-established by the formation of new nerve endings.
General characteristics of the active substance
Using currently available analytical technology, it is not possible to detect XEOMIN in the peripheral blood following intramuscular injection at the recommended doses.
XEOMIN has been investigated in a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, TWSTRS severity score ≥ 10, TWSTRS disability score ≥ 3, and TWSTRS pain score ≥ 1. For patients who had previously received a botulinum toxin treatment for cervical dystonia, the trial required that ≥ 10 weeks had passed since the most recent botulinum toxin administration. Patients with swallowing disorders or any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (1:1:1) to receive a single administration of XEOMIN 240 Units (n=81), XEOMIN 120 Units (n=78), or placebo (n=74). Each patient received a single administration of 4.8 mL of reconstituted study agent (XEOMIN 240 Units, XEOMIN 120 Units, or placebo). The investigator at each site decided which muscles would receive injections of the study agent, the number of injection sites, and the volume at each site. The muscles most frequently injected were the splenius capitis/semispinalis, trapezius, sternocleidomastoid, scalene, and levator scapulae muscles. Table 5 indicates the average XEOMIN dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trial.
Table 5: XEOMIN 120 Units Initial Dose (Units and % of the
Total Dose) by Unilateral Muscle Injected During Double Blind Pivotal Phase
|Number of Patients Injected Per Muscle||XEOMIN Dose Injected|
|Median XEOMIN Units||75th percentile XEOMIN Units|
|Splenius capitis/ Semispinalis capitis||78||48||63|
|Scalenus (medius and anterior)||27||20||25|
Most patients received a total of 2-10 injections into the selected muscles. Patients were assessed by telephone at one week post-injection, during clinic visits at Weeks 4 and 8, and then by telephone assessments or clinic visits every two weeks up to Week 20.
The mean age of the study patients was 53 years, and 66% of the patients were women. At study baseline, 61% of patients had previously received a botulinum toxin as treatment for cervical dystonia. The study was completed by 94% of study patients. Three patients discontinued the study prematurely due to adverse events: two patients in the 240 Unit group experienced musculoskeletal pain and muscle weakness, and one patient in the 120 Unit group experienced nausea and dizziness.
The primary efficacy endpoint was the change in the TWSTRS total score from baseline to Week 4 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's baseline value. In the ITT population, the difference between the XEOMIN 240 Unit group and the placebo group in the change of the TWSTRS total score from baseline to Week 4 was -9.0 points, 95% confidence interval (CI) -12.0; -5.9 points; the difference between the XEOMIN 120 Unit group and the placebo group in the change of the TWSTRS total score from baseline to Week 4 was -7.5 points, 95% CI -10.4; -4.6 points.
Figure 2 illustrates the cumulative percentage of patients from each of the three treatment groups who had attained the specified change in TWSTRS Score from baseline versus 4 weeks post-injection. Three change scores have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown.
Figure 2: Cumulative Percentage of Patients with Specified
Changes from Baseline TWSTRS Total Score at Week 4
The curves demonstrate that both patients assigned to placebo and XEOMIN have a wide range of responses, but that the active treatment groups are more likely to show greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo.
Comparison of each XEOMIN group to the placebo group was statistically significant at p < 0.001. Initial XEOMIN doses of 120 Units and 240 Units demonstrated no significant difference in effectiveness between the doses. . The efficacy of XEOMIN was similar in patients who were botulinum toxin na´ve and those who had received botulinum toxin prior to this study.
Examination of age and gender subgroups did not identify differences in response to XEOMIN among these subgroups. There were too few African-American patients to adequately assess efficacy in that population.
XEOMIN has been investigated in a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial in a total of 109 patients with blepharospasm. Patients had a clinical diagnosis of benign essential blepharospasm, with baseline Jankovic Rating Scale (JRS) Severity subscore ≥ 2, and a stable satisfactory therapeutic response to previous administrations of onabotulinumtoxinA (Botox). At least 10 weeks had to have elapsed since the most recent onabotulinumtoxinA administration. Patients with any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (2:1) to receive a single administration of XEOMIN (n=75) or placebo (n=34). Each patient in the XEOMIN group received a XEOMIN treatment (dose, volume, dilution, and injection sites per muscle) that was similar to the most recent onabotulinumtoxinA injection sessions prior to study entry. The highest dose permitted in this study was 50 Units per eye; the mean XEOMIN dose was 33 Units per eye.
In Table 6 the most frequently injected sites, the median dose per injection site, and the median number (and range) of injection sites per eye are presented.
Table 6: Median Dose and Median Number of Injection Sites
per Eye (Blepharospasm)
|Injection Area||Median Units XEOMIN||Median Number of Injection Sites (Min-Max)|
|Temporal Area||13||2 (1 – 6)|
|Eyebrow Area||5||1 (1 – 4)|
|Upper Lid Area||10||2 (1 – 4)|
|Lower Lid Area||8||2 (1 – 3)|
|Orbital Rim||5||1 (1 – 3)|
Patients were assessed during clinic visits at Weeks 3 and 6, and then by telephone or at clinic visits every two weeks up to Week 20.
The mean age of the study patients was 62 years, and 65% of the patients were women. The study was completed by 94% of study patients. Approximately one third of patients had other dystonic phenomena; in all but 1% this was limited to facial, cervical, perioral and mandibular muscles. No patients discontinued the study prematurely due to adverse events.
The primary efficacy endpoint was the change in the JRS Severity subscore from baseline to Week 6 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's most recent value (i.e., last observation carried forward). In the ITT population, the difference between the XEOMIN group and the placebo group in the change of the JRS Severity subscore from baseline to Week 6 was -1.0 (95% CI -1.4; -0.5) points. Comparison of the XEOMIN group to the placebo group was statistically significant at p < 0.001.
Figure 3: Frequency Distribution of Changes from Baseline
JRS Severity Subscore at Week 6
Examination of age and gender subgroups did not identify substantial differences in response to XEOMIN among these subgroups. There were too few African- American patients to assess efficacy in that population.
Two identically designed randomized, double-blind, multi-center, placebo controlled clinical trials (Studies GL-1 and GL-2) were conducted to evaluate XEOMIN for use in the temporary improvement of moderate to severe glabellar lines. The studies enrolled 547 healthy patients ( ≥ 18 years old) with glabellar lines of at least moderate severity at maximum frown. Three hundred sixty six subjects were treated with 20 U of XEOMIN and 181 subjects were treated with placebo. Subjects were excluded if they had marked ptosis, deep dermal scarring, or an inability to lessen glabellar lines, even by physically spreading them apart. The mean age of study subjects was 46 years. The majority of patients were female (86% and 93% in Studies GL-1 and GL-2, respectively), and predominantly Caucasian (89% and 65% respectively). The study subjects received either 20 U of XEOMIN or an equal amount of placebo. The total dose was delivered in 5 equally divided intramuscular injections of 4 Units each to specific sites (see Figure 1). Subjects were followed up for 120 days.
Investigators and subjects assessed efficacy at maximum frown on Day 30 of treatment using a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Composite treatment success was defined as a 2-grade improvement on this scale compared to baseline for both the investigator's and subject's assessments on Day 30. The percentage of subjects with treatment success was greater on the XEOMIN arm than the placebo arm at Day 30 in both studies (see Table 7). The percentage of subjects with composite treatment success at each visit are presented in Figure 4.
Table 7: Treatment Success at Day 30 (at Least 2 Grades Improvement
from Baseline at Maximum Frown)
|Composite Treatment Success*||111 (60%)||0 (0%)||87 (48%)||0 (0%)|
|Investigator Assessment||141 (77%)||0 (0%)||129 (71%)||0 (0%)|
|Subject Assessment||120 (65%)||0 (0%)||101 (55%)||1 (1%)|
|* Success on both the Investigator and Subject Assessments|
Figure 4: Percentage of Subjects with Composite Treatment
Success by Visit – Observed Cases (GL-1 and GL-2)
Last reviewed on RxList: 8/9/2011
This monograph has been modified to include the generic and brand name in many instances.
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