What is BOTOX®?
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex is a therapeutic muscle-relaxing agent that helps reduce the uncontrollable muscular contractions and associated pain that characterize cervical dystonia. It belongs to a class of drugs called neurotoxins.
BOTOX® is the brand name of a unique product that is available only from Allergan. It is not interchangeable with other products that contain botulinum neurotoxin. BOTOX® inhibits the nerve impulses that trigger muscle hyperactivity. By relaxing hyperactive neck and shoulder muscles, BOTOX® injection can improve head position and reduce pain in patients with cervical dystonia.1
I’ve heard that BOTOX® was recently approved for the treatment of cervical dystonia. Dose this mean that it is a new treatment?
No. Botulinum toxin type A has been endorsed by the National Institutes of Health (NIH) and the American Academy of Neurology (AAN) since 1990 as a valuable treatment for cervical dystonia.2,3 Tens of thousands of dystonia patients have received BOTOX® injections worldwide. In December 2000, the United States Food and Drug Administration (US FDA) approved BOTOX® as a treatment to decrease the severity of abnormal head position and neck pain associated with cervical dystonia in adults. As a result, Allergan now can inform doctors, pharmacists, payers, and insurers about the use of BOTOX® for treating cervical dystonia. Although 95% of payers already reimburse BOTOX® for the treatment of cervical dystonia, US FDA approval will help Allergan’s reimbursement specialists secure coverage from the remaining payers who currently deny coverage.
What are the different botulinum neurotoxin serotypes?
Botulinum toxin type A is 1 of 7 distinct botulinum neurotoxin serotypes referred to alphabetically as A, B, C1, D, E, F, and G. Each serotype has different properties and actions. No two botulinum products are alike.
The serotypes were first distinguished in the early 1900s when scientists noticed that animals showed certain distinct biological responses to botulinum toxins obtained from different sources.4 These researchers called the two different botulinum toxins types A and B.
Botulinum toxin type A was the first serotype developed for clinical use and is still the most studied of the 7 serotypes. The unique properties of BOTOX® result from both the A serotype, which is the most studied, and the unique Allergan manufacturing processes updated in 1997. (For more information please see the question regarding the difference between original and current BOTOX®)
How long can I be treated with BOTOX® for cervical dystonia?
Cervical dystonia is a chronic condition that typically requires long-term treatment. For this reason, it is very important to preserve long-term responsiveness to therapy. Although most patients continue to respond to BOTOX® injections, some patients may experience a diminished response over time.
There are several reasons why you may feel that you’re not getting the same benefit you got early on with botulinum toxin therapy.
The original pattern of your muscle hyperactivity may have changed.5,6 According to noted movement disorder specialist, Dr. Drake Duane: “The character of the movement may change over time.”7 For most patients, the change in muscle contractions does not result in a change in head posture or the direction of turning. However, head position may change for some patients.5
If the pattern of your muscle activity changes, your doctor may need to adjust the BOTOX® injections to target the new muscles. In a 1991 article, Dr. Douglas Gelb and his colleagues recommended that doctors perform muscle activity tests in patients who no longer respond to previously effective doses. This allows your doctor to identify the overactive muscles and adjust your injection sites accordingly.6 Depending on the results, your doctor may also have to change your BOTOX® dose.
You may believe that your first BOTOX® injection was more helpful than subsequent injections.8 There are several possible explanations for this perception. According to Dr. Allison Brashear, a movement disorder specialist at Indiana University Hospital, patients may not want to wait until their symptoms return to their original severity before receiving their next injection. Dr. Brashear also explains that patients may perceive more benefit with the first BOTOX® injection because they may have experienced more severe pain and pulling in the neck before the first treatment.
In these cases, the difference between a patient’s condition before and after injection is less pronounced than if the patient allowed his or her head position and pain to completely return to its pretreatment severity. In other words, the maximal improvement with BOTOX® injections may not have changed over time. Instead, patients may be starting from a better head position and less severe pain with subsequent injections.
Botulinum toxins are proteins. Under certain conditions, it is natural for your body to form antibodies to foreign proteins. These antibodies may interfere with the ability of BOTOX® to work effectively. If you develop antibodies to BOTOX® or other botulinum toxins you may stop responding to the therapy.
How can I help maintain my response to BOTOX® over the long term?
Minimizing the risk of antibody formation may help to maintain clinical response to BOTOX® over the long term. The factors that contribute to neutralizing antibody formation have not been well characterized. However, several of the factors that have been associated with antibody formation are individual genetic characteristics and overall exposure to neurotoxin complex protein.
Some individuals have a predisposition toward antibody formation because of certain genetic characteristics. Although it is not currently possible to control these individual genetic characteristics, doctors can control the overall amount of neurotoxin complex protein to which you are exposed. There are at least 3 important features of neurotoxin complex protein load exposure.
Protein Load Per Effective Dose. Exposure to higher amounts of foreign proteins is associated with a higher risk of antibody formation.9 Although well-controlled clinical studies with BOTOX® have not been conducted, the results of several retrospective studies suggest that the association between higher protein exposure and increased risk of antibody formation holds true for botulinum toxins.10,11 Dr. Jankovic and his colleagues performed a retrospective comparison of 20 cervical dystonia patients who developed antibodies and 22 who did not. They concluded that there is “a link among the mean dose per treatment session, total cumulative dose, and the development of BTX [botulinum toxin] antibodies.”11 As total dose is increased, so is exposure to neurotoxin complex protein. Although this study was not designed in a way that directly links protein and antibody formation, it does support this idea.
Frequency of Exposure. Frequent injections of a foreign protein have been shown to increase the body’s immune response.13 This suggests that frequent injections of botulinum neurotoxins may also increase the risk of antibody formation. In one retrospective study, investigators compared a group of 8 patients who had stopped responding to treatment to 32 patients who were still responding.12 The nonresponders had received more frequent injections and a higher percentage of booster injections than the responders. Based on these results, Dr. Greene and his colleagues concluded that, “In order to minimize the risk of developing BTX resistance ¼ we recommend that physicians wait as long as possible ¼ between BTX injections, avoid booster injections, and use the smallest possible doses.” 12 Although this study was not designed in a way that directly links the frequency of injections and antibody formation, it does support this idea.
Dosing Experience. As doctors gain experience with a given product, they may be able to better select the lowest effective dose for their patients and treat at the longest possible injection intervals. By delivering the lowest amount of neurotoxin complex protein to patients it may be possible to reduce the risk of antibody formation.
What is the difference between original and current BOTOX®?
Original BOTOX® was used clinically from 1989 to 1997. In November 1997, the US FDA approved the current preparation of BOTOX®. Original BOTOX® contained approximately 25 nanograms of neurotoxin complex protein per 100 units. In contrast, current BOTOX®, which is more active than the original BOTOX®, contains approximately 5 nanograms of neurotoxin complex protein per 100 units.
Why is this important?
The amount of botulinum toxin type A protein per dose is important because high protein loads have been linked to the formation of antibodies.10,11
In a study of 192 cervical dystonia patients with an average disease duration of 11 years and who had received multiple treatments with original BOTOX®, 17% had neutralizing antibodies at study entry.1 Although the antigenic potential of current BOTOX® has not been fully studied, it is predicted to have a lower antigenic potential than the original product due to its significantly reduced protein load.
For example, current BOTOX® results in a protein load of approximately 12 nanograms of protein per injection, based on a dose of 236 units (the average dose used in the BOTOX® phase 3 study for cervical dystonia1). This protein load is comparable to that received by blepharospasm patients injected with original BOTOX®. Since antibody formation in blepharospasm patients treated with the original product was relatively uncommon, it may be predicted that cervical dystonia patients treated with current BOTOX® may also show a low rate of antibody formation. If this prediction is true, cervical dystonia patients may be less likely to develop neutralizing antibodies.
What conditions does BOTOX® treat?
In the United States, BOTOX® is approved for the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and associated neck pain. BOTOX® is also indicated for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.
What side effects might I experience with BOTOX® treatment?
As a result of more than 10 years of clinical experience, physicians have learned a lot about how to use BOTOX® to get the best effects with the fewest adverse events. The most frequently reported adverse reactions associated with BOTOX® therapy include dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%).1
Is BOTOX® approved in any other countries?
BOTOX® is approved by the health ministries of 69 countries outside of the United States for the treatment of one or more disorders. Research on more than 50 different diseases or disorders has been published in approximately 2600 articles.
What’s the bottom line?
It’s important to discuss your treatment needs with your doctor. Doctors experienced with BOTOX® treatments can help you maximize your treatment benefits. By understanding some of the factors that help maintain long-term response, you may be able to get the best possible results from your BOTOX® injections over the longest possible time.
BOTOX® US Package Insert.
US Dept of Health and Human Services. Botulinum Toxin. Consensus Statement. NIH Consensus Development Conference; November 12-14, 1990. Bethesda, Md: National Institutes of Health; 1990.
Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology. 1990;40:1332-1336.
Burke GS. Notes on Bacillus botulinus. J Bacteriol. 1919;4:555-565.
Chan J, Brin MF, Fahn S. Idiopathic cervical dystonia: clinical characteristics. Mov Disord. 1991;6:119-126.
Gelb DJ, Yoshimura DM, Olney RK, Lowenstein DH, Aminoff MJ. Change in pattern of muscle activity following botulinum toxin injections for torticollis. Ann Neurol. 1991;29:370-376.
Duane DD. Spasmodic torticollis. In Advances in Neurology. 49: Facial Dyskinesias. J Jankovic, E. Tolosa, eds. 1988;Raven Press, New York. 135-150.
Brashear A, Bergan K, Wojcieszek J, Siemers ER, Ambrosius W. Patients’ perception of stopping or continuing treatment of cervical dystonia with botulinum toxin type A. Mov Disord. 2000;15(1):150-153.
Rosenberg JS, Middlebrook JS, Atassi MZ. Localization of the regions on the C-terminal domain of the heavy chain of botulinum toxin A recognized by T lymphocytes and by antibodies after immunization of mice with pentavalent toxoid. Immunol Invest. 1997;26:491-504.
Hatheway CL, Dang C. Immunogenicity of neurotoxins of Clostridium botulinum. In: Jankovic J, Hallett M, eds. Therapy with Botulinum Toxin. New York: Marcel Dekker; 1994; 93-107.
Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology. 1995;45:1743-1746.
Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord. 1994;9:213-217.
Submitted by Allergan Pharmaceutical
My mom and I wanted to thank you for hosting such a great symposium this year. This was our third year and we are looking forward to next years. E. Mathews