Neurotoxins Licensed As Treatment for Neck Neuromuscular Disorder
Allergan markets botulinum toxin type A (Botox), produced by fermentation of the Hall strain of Clostridium botulinum. This product has been available since 1989 for the treatment of blepharospasm and strabismus associated with dystonia in people at least 12 years old. Elan Pharmaceuticals will market botulinum toxin type B (Myobloc [PDF]), produced by fermentation of the Bean strain of C. botulinum. Both biological products contain their respective toxin in association with accessory proteins.
Botulinum toxins block neuromuscular transmission, and hence muscle contraction, by inhibiting the release of acetylcholine from motor neurons. Type A toxin cleaves synaptosome-associated protein, and type B toxin cleaves synaptic vesicle-associated membrane protein. When used at a therapeutic dose, botulinum toxin type A has been shown to partially denervate the treated muscle, resulting in less activity; however, this chemical denervation may not be permanent.
The effectiveness of botulinum toxin type A for the treatment of cervical dystonia was demonstrated in a multicenter, randomized, double-blind trial in adults who had responded well to previous therapy with the neurotoxin. Abnormal head positioning six weeks after treatment was judged to be less severe among the patients who received another injection of the neurotoxin, compared with the patients who received placebo. Also after six weeks, 51% of the neurotoxin-treated patients but 31% of the placebo group had improved. Most of the 88 patients in the neurotoxin group received injections into three or four muscles.
Two multicenter, randomized, double-blind studies were conducted with botulinum toxin type B. All 186 adults had responded well to previous therapy with botulinum toxin type A, although 77 of them no longer did. Four weeks after treatment, patients who received a total of 5,000 or 10,000 units of botulinum toxin type B in two to four muscles showed significant overall improvement in the severity of abnormal head positions, severity and duration of pain due to dystonia, and disability compared with the placebo group. The patients who had lost responsiveness to the type A toxin received only the 10,000-unit dose or placebo.
At FDA's request, the companies will each conduct a postmarketing study to evaluate the safety and antigenicity of their product two years after administration to at least 250 patients with cervical dystonia. Investigations have shown that some patients produce antibodies to the neurotoxin. Elan must also study the stability of its product. Descriptions of two other studies to be conducted by Elan were deleted from the publicly accessible copy of the FDA approval letter.
The botulinum toxins are contraindicated in people hypersensitive to any ingredient in the formulations. Botulinum toxin type A is also contraindicated if there is an infection at the proposed injection site. Even at doses recommended in the package labeling, neurotoxin should only be administered with caution to people with a peripheral motor neuropathic disease such as amyotrophic lateral sclerosis or a neuromuscular junctional disorder such as myasthenia gravis; these patients are at increased risk for severe dysphagia, respiratory compromise, and other systemic effects of botulinum toxins.
Patients with cervical dystonia commonly report dysphagia after treatment with botulinum toxin. In rare cases the dysphagia has been severe enough to warrant the insertion of a gastric feeding tube. Upper-respiratory-tract infection, neck pain, or headache occurred in more than 10% of patients who received botulinum toxin type A; dry mouth, neck pain, injection-site pain, infection, or headache occurred in more than 10% of patients who received botulinum toxin type B. Adverse effects generally occur in the first week after treatment and may last for several months. Although both neurotoxins cause botulism, the labeling for botulinum toxin type B states that no cases have been documented after intramuscular injection of the neurotoxin in patients with cervical dystonia who were enrolled in the clinical trials.
The labeling for botulinum toxin type A recommends that clinicians have epinephrine available in case an anaphylactic reaction occurs. Patients should be told to seek immediate medical attention if, after treatment, they have problems swallowing, speaking, or breathing. Deaths, some associated with dysphagia, have been reported after treatment with botulinum toxin.
Aminoglycosides and other agents that can interfere with neuromuscular transmission should be administered only with caution to patients also receiving neurotoxin therapy. The effect of switching botulinum toxins before the previous dose's effects have completely resolved are unknown; excessive neuromuscular weakness could result.
An equine-based trivalent antitoxin containing antibodies to serotypes A, B, and E is available from the Centers for Disease Control and Prevention (telephone 404-639-3670 8 a.m. to 4:30 p.m. EST; 404-639-2888 nights, weekends, or holidays) to counteract an overdose or injection into the wrong muscle. The antitoxin can prevent but not reverse toxin-induced muscle weakness.
Although pharmacokinetic tests have not been conducted, intramuscular injection of botulinum toxin at doses mentioned in the product labeling is not expected to produce a measurable blood concentration. Likewise, intramuscular injection of neurotoxin in accordance with the product labeling should not produce systemic effects in patients who do not have a neuromuscular dysfunction other than cervical dystonia.
The botulinum toxins are standardized on the basis of their biological activity in mice. Because the assay methods are product specific, the units of biological activity for the two toxins are not comparable.
The doses given in the Phase III trials should not be used as the starting point for treatment-naive patients. For these patients, the labeling for botulinum toxin type A seems to suggest a starting dose of <198 units, divided among the affected muscles; in the Phase III trial, the mean total dose was 236 units, and the dose for 75% of the patients was >198 units. The recommended starting dose of botulinum toxin type B is 2,5005,000 units, divided among the affected muscles, for patients who have tolerated previous botulinum toxin injections and <2,500 units for treatment-naive patients. After administration of botulinum toxin type A, patients should note some benefit within two weeks and feel maximum benefit at about six weeks, with the effect wearing off three months after the injection. A 5,000- to 10,000-unit dose of botulinum toxin type B exerts its effect for 1216 weeks.
Botulinum toxin type A is provided as a vacuum-dried powder in single-use vials containing 100 units of the neurotoxin complex, 0.5 mg of human albumin, and 0.9 mg of sodium chloride. Unopened vials must be stored at or below 5 degrees Celsius. Once reconstituted by gently adding preservative-free 0.9% sodium chloride injection to the powder, the clear, colorless solution should be stored at 28 degrees Celsius and used within four hours. Instructions are provided on adding sufficient diluent to yield doses of 0.1 mL per intramuscular injection. The solution should not be frozen or shaken.
Botulinum toxin type B is provided as a clear, colorless to light yellow solution in single-use vials without a preservative. The product contains 5000 units of the neurotoxin per milliliter in a solution of 0.05% human albumin, 0.01 M sodium succinate, and 0.1 M sodium chloride and is supplied in 3.5-mL vials containing 0.5, 1, or 2 mL of solution. Vials must be stored at 28 degrees Celsius; the solution must not be frozen or shaken. Upon dilution with 0.9% sodium chloride injection, the solution must be used within four hours.