"The U.S. Food and Drug Administration today approved Dotarem (gadoterate meglumine) for use in magnetic resonance imaging (MRI) of the brain, spine and associated tissues of patients ages 2 years and older.
Dotarem is a gadolinium-based"...
The seven serologically distinct botulinum neurotoxins, designated A through G, share a common structural organization consisting of one Heavy Chain and one Light Chain polypeptide linked by a single disulfide bond. These toxins inhibit acetylcholine release at the neuromuscular junction via a three stage process: 1) Heavy Chain mediated neurospecific binding of the toxin, 2) internalization of the toxin by receptor-mediated endocytosis, and 3) ATP and pH dependent translocation of the Light Chain to the neuronal cytosol where it acts as a zinc-dependent endoprotease cleaving polypeptides essential for neurotransmitter release. MYOBLOC (botulinum toxin type b) specifically has been demonstrated to cleave synaptic Vesicle Associated Membrane Protein (VAMP, also known as synaptobrevin) which is a component of the protein complex responsible for docking and fusion of the synaptic vesicle to the presynaptic membrane, a necessary step to neurotransmitter release.
Using currently available analytical technology, it is not possible to detect MYOBLOC (botulinum toxin type b) in the peripheral blood following intramuscular injection at the recommended doses.
Two phase 3, randomized, multi-center, double-blind, placebo controlled studies of the treatment of cervical dystonia were conducted. Both studies enrolled only adult patients who had a history of receiving botulinum toxin type A in an open label manner, with a perceived good response and tolerable adverse effects. Study #301 enrolled patients who were perceived as having an acceptable response to type A toxin, while Study #302 enrolled only patients who had secondarily lost responsiveness to type A toxin. Other eligibility criteria common to both studies were that all subjects had moderate or greater severity of cervical dystonia with at least 2 muscles involved, no neck contractures or other causes of decreased neck range of motion, and no history of any other neuromuscular disorder. Subjects in Study #301 were randomized to receive placebo, 5,000 Units or 10,000 Units of MYOBLOC (botulinum toxin type b) , and subjects in Study #302 were randomized to receive placebo or 10,000 Units of MYOBLOC (botulinum toxin type b) . Study agent was administered to subjects in a single treatment session by investigators who selected 2 to 4 muscles per subject from the following: Splenius capitis, Sternocleidomastoid, Levator scapulae, Trapezius, Semispinalis capitis, and Scalene muscles. The total dose was divided between the selected muscles, and from 1 to 5 injections were made per muscle. There were 109 subjects enrolled into Study #301, and 77 into Study #302. Patient evaluations continued for 16 weeks post injection.
The primary efficacy outcome variable for both studies was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total Score (scale range of possible scores is 0–87) at Week 4. TWSTRS is comprised of three sub-scales which examine 1) Severity—the severity of the patient's abnormal head position; 2) Pain—the severity and duration of pain due to the dystonia; and 3) Disability— the effects of the abnormal head position and pain on a patient's activities. The secondary endpoints were the Patient Global and Physician Global Assessments of change at Week 4. Both Global Assessments used a 100-point visual-analog scale (VAS). The Patient Global Assessment allows patients to indicate how they feel at the time of their evaluation compared to the pre-injection baseline. Likewise, the Physician Global Assessment indicates the physician's assessment of a patient's change from baseline to Week 4. Scores of 50 indicate no change, 0 much worse, and 100 much better. Results of comparisons of the primary and secondary efficacy variables are summarized in Table 1.
Table 1: Efficacy Results From Two Phase 3 MYOBLOC (botulinum toxin type b) Studies
|Assessments*||STUDY 301||STUDY 302|
n = 36
| 5,000 Units
n = 36
| 10,000 Units
n = 37
n = 38
| 10,000 Units
n = 39
|Mean at Baseline||43.6||46.4||46.9||51.2||52.8|
|Change from Baseline||-4.3||-9.3||-11.7||-2.0||-11.1|
|95% Confidence Interval||(-8.9, -1.2)||(-11.1, -3.3)||(-12.2, -5.2)|
|Mean at Week Four||43.6||60.6||64.6||39.5||60.2|
|95% Confidence Interval||(7.0, 26.9)||(11.3, 31.1)||(11.2, 29.1)|
|Mean at Week Four||52.0||65.3||64.2||47.9||60.6|
|95% Confidence Interval||(5.5, 21.3)||(3.9, 19.7)||(7.4, 18.1)|
|Mean at Baseline||18.4||20.2||20.2||22.1||22.6|
|Change from Baseline||-2.3||-3.2||-4.8||-1.2||-3.7|
|95% Confidence Interval||(-2.5, 0.6)||(-4.0, -1.0)||(-3.9, -1.0)|
|Mean at Baseline||10.9||11.8||12.4||12.2||11.9|
|Change from Baseline||-0.5||-3.6||-4.2||-0.2||-3.6|
|95% Confidence Interval||(-4.7, -1.1)||(-5.1, -1.4)||(-5.0, -2.1)|
|Mean at Baseline||14.3||14.4||14.4||16.9||18.3|
|Change from Baseline||-1.6||-2.5||-2.7||0.8||-3.8|
|95% Confidence Interval||(-2.7, 0.7)||(-2.8, 0.6)||(-4.1, -1.0)|
|* 95% Cl are for the differences between the active and placebo groups. The P values are for the comparison of active dose and placebo. For TWSTRS-Total and TWSTRS-subscale scores, P values are from ANCOVA for each variable with center and treatment in the model and the baseline value of the variable included as a covariate. For the Patient Global and Physician Global Assessments, P values are from ANOVA for each variable with center and treatment in the model.|
There were no statistically significant differences in results between the 5,000 Units and 10,000 Units doses in Study #301. Exploratory analyses of these two studies suggested that the majority of patients who showed a beneficial response by Week 4 had returned to their baseline status between Weeks 12 to 16 post injection. Although there was a MYOBLOC (botulinum toxin type b) associated decrease in pain, there remained many patients who experienced an increase in dystonia-related neck pain irrespective of treatment group (see ADVERSE REACTIONS). TWSTRS Total Score at Week 4 and Patient Global Assessment among subgroups by gender or age showed consistent treatment-associated effects across these subgroups (see also PRECAUTIONS: Geriatrics). There were too few non-Caucasian patients enrolled to draw any conclusions regarding relative efficacy in racial subsets.
MYOBLOC (botulinum toxin type b) was studied in two phase 2 dose ranging studies, Studies #08 and #09, which preceded the phase 3 studies. Studies #08 and #09 had a study design similar to the phase 3 studies, including eligibility criteria. Study #08 enrolled 85 subjects randomized between doses of placebo, 400 Units, 1,200 Units, or 2,400 Units (21 or 22 subjects per group). Study #09 enrolled 122 subjects and randomized between doses of placebo, 2,500 Units, 5,000 Units, and 10,000 Units (30 or 31 subjects per group). These studies demonstrated efficacy on the TWSTRS-Total, baseline to Week 4, at doses of 2,400 Units, 2,500 Units, 5,000 Units, and 10,000 Units. Study #08 showed mean improvement from baseline on the Week 4 TWSTRS for placebo and 2,400 Units of 2.0 and 8.5 points respectively (from baselines of 42.0 and 42.4 points). Study #09 showed mean improvement from baseline to Week 4 for placebo, 2,500 Units, 5,000 Units, and 10,000 Units of 3.3, 11.6, 12.5, and 16.4 points, respectively (from baselines of 45.5, 45.6, 45.2, and 47.5 points). Study #08 also indicated there is less response for doses below 2,400 Units.
Study #352 was an open label, intrapatient dose-escalation study of 3 treatment sessions where each patient with cervical dystonia sequentially received 10,000 Units, 12,500 Units, and 15,000 Units, at periods of 12 to 16 weeks between treatment sessions irrespective of their response to their previous dose. This study enrolled 145 patients, of whom 125 received all three treatments. Although this was an open label design where investigators and patients knew the dose at each treatment session, there were similar mean improvements on the TWSTRS-Total, from baseline to Week 4, for all three doses.
In the MYOBLOC (botulinum toxin type b) injected patients (n=112) of the phase 3 studies, 19% had 2 muscles injected, 48% had 3 muscles injected, and 33% had 4 muscles injected. Table 2 indicates the frequency of use for each of the permitted muscles, and the fraction of the total dose of the treatment injected into each muscle, for those patients in whom the muscle was injected.
Table 2: Studies 301 and 302 Combined Data Fraction of Total
Dose Injected into Involved Muscles
|Muscle Injected||Percent Frequency Injected*||Fraction of Total Dose Injected by Percentiles|
|* Percent frequency of patients in whom each muscle was injected|
Last reviewed on RxList: 8/14/2009
This monograph has been modified to include the generic and brand name in many instances.
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