Overview of Botulinum Toxin Products

Anaheim—In the past 2 decades, the US Food and Drug Administration (FDA) has approved 4 products containing botulinum toxin; it has also required a risk evaluation and mitigation strategy (REMS) for each product: onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB. The FDA warns about the risk of spreading the potent toxin and provides guidelines and advice on how to best care for patients using the products. Pharmacists discussed the REMS program as well as the safety and efficacy of the products at the ASHP meeting during a symposium titled Current Considerations for the Safe Use of Botulinum Toxin. Evelyn Hermes DeSantis, PharmD, BCPS, director of the Drug Information Center at the Robert Wood Johnson University Hospital, Piscataway, New Jersey, said there are 7 serotypes of botulinum toxin but only 2 (serotype A and B) are used therapeutically and are commercially available. Botulinum toxin serotype A and B range from 300 to 900 kDa and produce temporary chemical denervation and relaxation of the striated muscle. However, the toxins’ molecular structure and intracellular targets are different. Botulinum toxin serotype A’s receptor target is synaptosomal-associated protein 25, while botulinum toxin serotype B’s receptor target is vesicleassociated membrane protein. OnabotulinumtoxinA comes in single-use vials of 100 and 200 units, and its average wholesale price (AWP) is $630/100 units. AbobotulinumtoxinA comes in a single-use vial of 100 units, and its AWP is $852/500 units. IncobotulinumtoxinA comes in singleuse vials of 50 and 100 units, and its AWP is $320/50 units. RimabotulinumtoxinB comes in single-use vials of 2500 units (0.5 mL), 5000 units (1 mL), and 10,000 units (2 mL), and its AWP is $609/5000 units. Joyce Generali, MS, BSPharm, FASHP, clinical professor in the University of Kansas’s School of Pharmacy, Kansas City, discussed the safety concerns related to botulinum toxin products. Public Citizen, a nonprofit organization, distributed a petition in June 2008 requesting the FDA to write warning letters to physicians about botulinum toxin products to emphasize that distant spread is possible, people have died from using botulinum toxin products, and the cosmetic form of botulinum toxin products may cause dysphagia and aspiration. The group asked the FDA to have medication guides dispensed with the products. In August 2009, the FDA released a safety warning establishing name changes for the products, reinforcing individual potencies and prevention of medication errors, reviewing the boxed warning regarding potentially life-threatening issues, reviewing the REMS program, and making healthcare professionals, patients, family members, caregivers, and the public aware of the issues. The FDA also made it mandatory for botulinum toxin products to contain a black box warning alerting patients that the products may spread from the area of the injection and produce symptoms associated with botulinum toxin effect that may occur within hours or weeks of the injection. The black box warning also tells patients that there have been cases where people have died and have had life-threatening swallowing or breathing difficulties. Children treated for spasticity are at the highest risk of adverse events, but they can also occur in adults with underlying conditions predisposing them to the symptoms. The REMS program was created as part of the FDA Amendments Act of 2007. The legislation granted the FDA the authority to require a REMS program be submitted to ensure that a drug’s benefits outweigh its risks. A REMS program includes a medication guide, communication plan for healthcare providers, and elements that ensure safe use of the product as well as requirements for people who prescribe, dispense, or use the drug. According to Ms. Generali, the goals for the botulinum toxin REMS program are to minimize the risk of medication errors related to the lack of interchangeability and to inform prescribers and patients that the toxin may spread beyond the injection site. Dr. DeSantis then returned to the podium to discuss an evidence-based approach to patient care. She said the FDA approved the first botulinum toxin product in 1991 to treat blepharospasm and strabismus, followed by cervical dystonia in 2000, axillary hyperhidrosis in 2004, and chronic migraine and upper limb spasticity in 2010. Dr. DeSantis said researchers have faced challenges in designing clinical trials for botulinum toxin products. They have trouble defining the diseases associated with the products and have had issues pertaining to inclusion and exclusion criteria, outcome measures, and placebo effects. Botulinum toxin products are used to treat spasticity, an involuntary muscle hyperactivity that occurs because of a brain or spinal cord injury. The therapies are intended to prevent deformities, improve function, and relieve symptoms in patients. Dr. DeSantis said there have been >100 published studies examining spasticity, but there are limitations to the evidence of how well botulinum toxin products work in treating the disease. According to Dr. DeSantis, the American Academy of Neurology (AAN) guidelines indicate that botulinum toxin products should be offered to adults suffering from spasticity as an optional course of action to reduce muscle tone and improve passive function and that the products should be considered to improve active function. She cautioned that additional trials are needed to compare botulinum toxin products with other drugs in evaluating active function. The AAN recommends that botulinum toxin products should be offered as an option to treat patients with cervical dystonia, characterized by involuntary cervical muscle contractions as well as abnormal movements and posture of the head. In addition, the AAN guidelines indicate botulinum toxin products should be offered as an option to treat patients with axillary hyperhidrosis (excessive and uncontrollable sweating of axillas). The AAN also says patients should have an option to use botulinum toxin products to treat blepharospasm, involuntary eye closure that affects 20,000 to 50,000 people in the United States. Finally, Ms. Generali concluded the symposium with an overview of the impact of botulinum toxin products on formulary management.