The most commonly reported adverse events associated with MYOBLOC (botulinum toxin type b) treatment in all studies were dry mouth, dysphagia, dyspepsia, and injection site pain. Dry mouth and dysphagia were the adverse reactions most frequently resulting in discontinuation of treatment. There was an increased incidence of dysphagia with increased dose in the sternocleidomastoid muscle. The incidence of dry mouth showed some dose-related increase with doses injected into the splenius capitis, trapezius and sternocleidomastoid muscles.
Only nine subjects without a prior history of tolerating injections of type A botulinum toxin have been studied. Adverse event rates have not been adequately evaluated in these patients, and may be higher than those described in Table 3.
Adverse reaction rates observed in the clinical trials for a product cannot be directly compared to rates in clinical trials for another product and may not reflect the rates observed in actual clinical practice. However, adverse reaction information from clinical trials does provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
MYOBLOC (botulinum toxin type b) was studied in both placebo controlled single treatment studies and uncontrolled repeated treatment studies; most treatment sessions and patients were in the uncontrolled studies. The data described below reflect exposure to MYOBLOC (botulinum toxin type b) at varying doses in 570 subjects, including more than 300 patients with 4 or more treatment sessions. Most treatment sessions were at doses of 12,500 Units or less. There were 57 patients administered a dose of 20,000 or 25,000 Units. All but nine patients had a prior history of receiving type A botulinum toxin and adequately tolerating the treatment to have received repeated doses.
The rates of adverse events and association with MYOBLOC (botulinum toxin type b) are best assessed in the results from the placebo controlled studies of a single treatment session with active monitoring. The data in Table 3 reflect those adverse events occurring in at least 5% of patients exposed to MYOBLOC (botulinum toxin type b) treatment in pooled placebo controlled clinical trials. Annual rates of adverse events are higher in the overall data which includes longer duration follow-up of patients with repeated treatment experience. The mean age of the population in these studies was 55-years-old with approximately 66% being female. Most of the patients studied were Caucasian and all had cervical dystonia that was rated as moderate to severe in severity.
Table 3: Treatment-Emergent AEs Reported by at Least 5% of MYOBLOC (botulinum toxin type b) Treated Patients by Dose Group, Following Single Treatment Session in Controlled Studies 09, 301 and 302
| Adverse Event
| 2,500 Units
| 5,000 Units
| 10,000 Units
|Dry Mouth||3 (3%)||1 (3%)||8 (12%)||36 (34%)|
|Dysphagia||3 (3%)||5 (16%)||7 (10%)||27 (25%)|
|Neck Pain related to CD*||17 (16%)||0 (0%)†||11 (16%)||18 (17%)|
|Injection Site Pain||9 (9%)||5 (16%)||8 (12%)||16 (15%)|
|Infection||16 (15%)||4 (13%)||13 (19%)||16 (15%)|
|Pain||10 (10%)||2 (6%)||4 (6%)||14 (13%)|
|Headache||8 (8%)||3 (10%)||11(16%)||12 (11%)|
|Dyspepsia||5 (5%)||1 (3%)||0 (0%)||11(10%)|
|Nausea||5 (5%)||3 (10%)||2 (3%)||9 (8%)|
|Flu Syndrome||4 (4%)||2 (6%)||6 (9%)||9 (8%)|
|Torticollis||7 (7%)||0 (0%)||3 (4%)||9 (8%)|
|Pain Related to CD/Torticollis||4 (4%)||3 (10%)||3 (4%)||7 (7%)|
|Arthralgia||5 (5%)||0 (0%)||1 (1%)||7 (7%)|
|Back Pain||3 (3%)||1 (3%)||3 (4%)||7 (7%)|
|Cough Increased||3 (3%)||1 (3%)||4 (6%)||7 (7%)|
|Myasthenia||3 (3%)||1 (3%)||3 (4%)||6 (6%)|
|Asthenia||4 (4%)||1 (3%)||0 (0%)||6 (6%)|
|Dizziness||2 (2%)||1 (3%)||2 (3%)||6 (6%)|
|Accidental Injury||4 (4%)||0 (0%)||3 (4%)||5 (5%)|
|Rhinitis||6 (6%)||1 (3%)||1 (1%)||5 (5%)|
| * Not a COSTART term
† Not collected in Study 09 by special COSTART term
In the overall clinical trial experience with MYOBLOC (botulinum toxin type b) (570 patients, including the uncontrolled studies), most cases of dry mouth or dysphagia were reported as mild or moderate in severity. Severe dysphagia was reported by 3% of patients. Severe dry mouth was reported by 6% of patients. Dysphagia and dry mouth were the most frequent adverse events reported as a reason for discontinuation from repeated treatment studies. These adverse events led to discontinuation from further treatments with MYOBLOC (botulinum toxin type b) in some patients even when not reported as severe.
The following additional adverse events were reported in 2% or greater of patients participating in any of the clinical studies (COSTART terms, by body system):
Body as a Whole: allergic reaction, fever, headache related to injection, chest pain, chills, hernia, malaise, abscess, cyst, neoplasm, viral infection; Musculoskeletal: arthritis, joint disorder; Cardiovascular System: migraine; Respiratory: dyspnea, lung disorder, pneumonia; Nervous System: anxiety, tremor, hyperesthesia, somnolence, confusion, pain related to CD/torticollis, vertigo, vasodilation; Digestive System: gastrointestinal disorder, vomiting, glossitis, stomatitis, tooth disorder; Skin and Appendages: pruritis; Urogenital System: urinary tract infection, cystitis, vaginal moniliasis; Special Senses: amblyopia, otitis media, abnormal vision, taste perversion, tinnitus; Metabolic and Nutritional Disorders: peripheral edema, edema, hypercholesterolemia; Hemic and Lymphatic System: ecchymosis.
The following adverse event has been reported during postmarketing use for approved and unapproved indications: constipation.
A two-stage assay was used to test for immunogenicity and neutralizing activity induced by treatment with MYOBLOC (botulinum toxin type b) . In order to account for varying lengths of follow-up, life-table analysis methods were used to estimate the rates of development of immune responses and neutralizing activity. During the repeated treatment studies, 446 subjects were followed with periodic ELISA based evaluations for development of antibody responses against MYOBLOC (botulinum toxin type b) . Only patients who showed a positive ELISA assay were subsequently tested for the presence of neutralizing activity against MYOBLOC (botulinum toxin type b) in the mouse neutralization assay (MNA). 12% of patients had positive ELISA assays at baseline. Patients began to develop new ELISA responses after a single treatment session with MYOBLOC (botulinum toxin type b) . By six months after initiating treatment, estimates for ELISA positive rate were 20%, which continued to rise to 36% at one year and 50% positive ELISA status at 18 months. Serum neutralizing activity was primarily not seen in patients until after 6 months. Estimated rates of development were 10% at one year and 18% at 18 months in the overall group of patients, based on analysis of samples from ELISA positive individuals. The effect of conversion to ELISA or MNA positive status on efficacy was not evaluated in these studies, and the clinical significance of development of antibodies has not been determined.
The data reflect the percentage of patients whose test results were considered positive for antibodies to MYOBLOC (botulinum toxin type b) in both an in vitro and in vivo assay. The results of these antibody tests are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity 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 antibodies to MYOBLOC (botulinum toxin type b) with the incidence of antibodies to other products may be misleading.