Dysport (AbobotulinumtoxinA) Now FDA Approved for the Treatment of Lower-Limb Spasticity in Adults

March 2018, Vol 11, Ninth Annual Payers' Guide - FDA Approvals, News & Updates
Lisa A. Raedler, PhD, RPh
Medical Writer
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Spasticity is a chronic condition that is characterized by an abnormal increase in tone or stiffness in ≥1 muscles that can interfere with movement and daily activities. Symptoms include rapid muscle contractions (clonus), exaggerated deep-tendon reflexes, muscle spasms, involuntary crossing of the legs (scissoring), and contractures.1 Typically caused by damage to nerve pathways in the brain or spinal cord, spasticity is often observed in patients with cerebral palsy, spinal cord injury, multiple sclerosis, stroke, or brain or head trauma.1 Lower-limb spasticity often involves spasticity in the gastrocnemius–soleus complex (GSC) muscle, which is located in the calf.

Treatment options for patients with spasticity are designed to improve physical function, alleviate pain, and minimize complications. The treatments for spasticity include drugs (eg, baclofen, diazepam, tizanidine, clonazepam), physical therapy to improve muscle stretching and range of motion, and tendon release surgery.1

Botulinum toxin is also used to treat spasticity.2 The clinical benefits of local injections of botulinum toxin, a nerve paralytic, have been documented since the late 1800s. Botulinum toxin acts by inhibiting acetylcholine release into muscles and weakening them. For patients with spasticity, this can result in improvements in range of motion and daily function.2

In 2010, onabotulinumtoxinA (Botox) became the first botulinum toxin type A (BoNT-A) drug to receive US Food and Drug Administration (FDA) approval for the treatment of adults with upper-limb spasticity, defined as increased muscle stiffness in the elbow, wrist, and fingers.3,4 In 2015, the FDA expanded the approval of onabotulinumtoxinA to include 2 thumb muscles for adults with upper-limb spasticity. In 2016, onabotulinumtoxinA was approved to decrease the severity of muscle stiffness in adults with lower-limb spasticity.3 IncobotulinumtoxinA (Xeomin) is another BoNT-A drug, which received a new indication in 2015 for the treatment of patients with upper-limb spasticity.5

Dysport Approved for Adults with Lower-Limb Spasticity

On June 16, 2017, the FDA granted expanded approval to abobotulinumtoxinA (Dysport; Ipsen), an injectable form of BoNT-A, for the treatment of adults with lower-limb spasticity.6,7 The expanded approval was based on a randomized, phase 3, double-blind, placebo-controlled clinical trial in adults with lower-limb spasticity after a stroke or a traumatic brain injury.6,7

AbobotulinumtoxinA was initially approved in July 2015 for the treatment of adults with upper-limb spasticity.7,8 In August 2016, the FDA approved abobotulinumtoxinA for use in children aged ≥2 years with lower-­limb spasticity.7,8

In addition, abobotulinumtoxinA is approved for other medical and cosmetic uses, including the treatment of adults with cervical dystonia, and for the temporary improvement in the appearance of moderate-to-severe glabellar lines associated with the procerus and corrugator muscle activity in adults aged <65 years.8

Mechanism of Action

AbobotulinumtoxinA inhibits the release of the neurotransmitter acetylcholine from peripheral cholinergic nerve endings.8 The subsequent chain of events in the motor nerves accounts for the therapeutic utility of this BoNT-A agent in diseases that are characterized by excessive efferent activity. Acetylcholine transmission recovers gradually as the neuromuscular junction recovers from exposure to the toxin and as new nerve endings are formed.8

Dosing and Administration

AbobotulinumtoxinA is administered by intramuscular injection. The dose of abobotulinumtoxinA is selected based on the muscles affected, the severity of muscle spasticity, any previous response to treatment, and a history of adverse reactions after treatment with abobotulinumtox­inA or with other BoNT-A drugs. Dosing for upper-limb spasticity is between 500 U and 1000 U, and dosing for lower-limb spasticity can range up to 1500 U. In adults, the maximum recommended total dose per treatment session (upper and lower limbs combined) is 1500 U.8

Repeat treatment with abobotulinumtoxinA should be administered when the effect of the previous injection has diminished, but no sooner than 12 weeks after the previous injection.8

Clinical Trial in Adults with Lower-Limb Spasticity

The efficacy of abobotulinumtoxinA in adults with lower-limb spasticity was established in a randomized, phase 3, double-blind, placebo-controlled clinical trial.9 Eligibility criteria included lower-limb spasticity, defined as Modified Ashworth Scale (MAS) score ≥2 in the affected ankle joint for BoNT-A–naïve patients, or MAS score ≥3 in the affected ankle joint for patients who received a BoNT-A drug at least 4 months since the last BoNT-A injection in the affected lower limb, and were at least 6 months poststroke or post–traumatic brain injury.9 The key efficacy measures were the change from baseline in the GSC muscle tone after 4 weeks, and the Physician Global Assessment score after 4 weeks.8,9

Overall, 381 patients were enrolled in the study, including 253 patients who received abobotulinumtoxinA and 128 who received placebo.9 Patients were randomized in a 1:1:1 ratio to receive abobotulinumtoxinA 1000 U, abobotulinumtoxinA 1500 U, or placebo. After a single injection, patients who received abobotulinumtoxinA showed improvement in muscle tone at the ankle joint based on reduced GSC muscle tone (Table).9 The duration of response was between 12 and 16 weeks for the majority of patients in the study.9

Table

Repeated, open-label administration of abobotulinumtoxinA for 1 year improved patients’ walking speed and their likelihood of achieving community ambulation.9 This is the first study to demonstrate functional improvements in gait and in quality of life in patients who receive repeated abobotulinumtoxinA injections in an open-label setting.9

Adverse Reactions

The most common (≥5%) adverse reactions in adults with lower-limb spasticity and that occurred more often in the abobotulinumtoxinA group than in the placebo group for abobotulinumtoxinA 1000 U, abobotulinumtoxinA 1500 U, and placebo, respectively, were falls (9%, 6%, 3%), muscular weakness (2%, 7%, 3%), and pain in extremity (6%, 6%, 2%).8

Muscular weakness was reported more frequently in women who received 1500 U of abobotulinumtoxinA compared with men who received this dose (10% vs 5%, respectively).8

Contraindications

AbobotulinumtoxinA is contraindicated in patients with hypersensitivity to any components or excipients of botulinum toxin components, in those with an allergy to cow’s milk protein, or with infection at the proposed injection site.8

Use in Specific Populations

AbobotulinumtoxinA may be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.8

No data are available regarding the presence of abo­botulinumtoxinA in human or animal milk, the effects on the breastfed infant, or the effects on milk production.8

Among patients with spasticity who participated in placebo-controlled clinical trials of abobotulinumtox­inA, 18% were aged ≥65 years; these older patients reported a higher incidence of adverse reactions compared with younger patients (46% vs 39%, respectively), specifically falls (10% vs 6%, respectively) and asthenia (4% vs 2%, respectively).8

Selected Warnings and Precautions

The prescribing information for abobotulinumtoxinA includes a boxed warning stating that the effects of botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism, including difficulties in swallowing or breathing, which can be life-threatening. The boxed warning specifies that the risk for these symptoms is probably greatest in children who receive treatment for spasticity, but symptoms can also occur in adults, particularly in those with underlying conditions that would predispose them to these symptoms.8

Because units of abobotulinumtoxinA are not interchangeable with other preparations of botulinum toxin drugs, units of biological activity of abobotulinumtoxinA cannot be compared with or converted into units of any other botulinum toxin drug assessed with any other specific assay method.8

Postmarketing safety data for approved botulinum toxin drugs, including abobotulinumtoxinA, suggest that botulinum toxin effects can be observed beyond the site of a local injection.8

Patients with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junction disorders (eg, myasthenia gravis or Lambert–Eaton syndrome) should be monitored particularly closely after botulinum toxin injection, because they may be at an increased risk for clinically significant side effects.8
Because abobotulinumtoxinA contains albumin, a derivative of human blood, it carries an exceptionally remote risk for transmission of viral diseases and variant Creutzfeldt–Jakob disease.8

Conclusion

AbobotulinumtoxinA is the only BoNT-A drug approved by the FDA for the treatment of adults with spasticity in both upper and lower limbs and for the treatment of lower-limb spasticity in children aged ≥2 years. This most recent approval by the FDA expands the population of patients who can benefit from abo­botulinumtoxinA to include adults with lower-limb spasticity associated with stroke, brain injury, or spinal cord injury.

References
1. National Institute of Neurological Disorders and Stroke. Spasticity information page. www.ninds.nih.gov/Disorders/All-Disorders/Spasticity-Information-­Page. Accessed March 7, 2018.
2. Davis EC, Barnes MP. Botulinum toxin and spasticity. J Neurol Neurosurg Psychiatry. 2000;69:143-147.
3. US Food and Drug Administration. Drugs@FDA: FDA approved drug products: onabotulinumtoxinA. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103000. Accessed March 8, 2018.
4. Das TK, Park DM. Effect of treatment with botulinum toxin on spasticity. Postgrad Med J. 1989;65:208-210.
5. US Food and Drug Administration. Drugs@FDA: FDA approved drug products: incobotulinumtoxinA. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125360. Accessed March 8, 2018.
6. Ipsen. Ipsen announces FDA approval of Dysport (abobotulinumtoxinA) for the treatment of lower limb spasticity in adults. June 16, 2017. www.ipsen.com/websites/IPSENCOM-PROD/wp-content/uploads/2017/06/16182401/16-06-2017-sNDA-DYSPORT-ALL-US-FINAL-1.pdf. Accessed March 8, 2018.
7. US Food and Drug Administration. Drugs@FDA: FDA approved drug products: abobotulinumtoxinA. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125274. Accessed March 8, 2018.
8. Dysport (abobotulinumtoxinA) for injection, for intramuscular use [prescribing information]. Basking Ridge, NJ: Ipsen Biopharmaceuticals; September 2017.
9. Gracies JM, Esquenazi A, Brashear A, et al; for the International AbobotulinumtoxinA Adult Lower Limb Spasticity study group. Efficacy and safety of abobotulinumtoxinA in spastic lower limb: randomized trial and extension. Neurology. 2017;89:2245-2253.

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