FDA Approves IncobotulinumtoxinA for Cervical Dystonia and Blepharospasm

Yael Waknine

August 03, 2010

August 3, 2010 — The US Food and Drug Administration (FDA) has approved incobotulinumtoxinA intramuscular injection (Xeomin; Merz Pharmaceuticals) for the treatment of botulinum toxin–naive and botulinum toxin–experienced adults with cervical dystonia to decrease the severity of abnormal head position and neck pain. It is also indicated to treat blepharospasm in adults previously treated with onabotulinumtoxinA (Botox; Allergan, Inc).

IncobotulinumtoxinA is a botulinum neurotoxin that is free from complexing proteins. It acts selectively on peripheral cholinergic nerve endings to inhibit the release of acetylcholine, thereby reducing muscle contraction.

Available in 50- and 100-Unit vials, incobotulinumtoxinA is the only botulinum toxin that does not require refrigeration before reconstitution, potentially simplifying product distribution and storage and helping to ensure product integrity at the time of injection.

Clinical Trials Support Drug Approval

FDA approval was based on data from 2 pivotal, phase 3 randomized, double-blind, placebo-controlled multicenter US studies and supported by findings from European studies comparing incobotulinumtoxinA with onabotulinumtoxinA.

In the first US study, investigators randomly assigned 233 patients with predominantly rotational cervical dystonia to receive 1 treatment session with incobotulinumtoxinA (total, 120 or 240 units) or placebo, most commonly injected into the splenius capitis, trapezius, sternocleidomastoid, scalene, and levator scapulae muscles.

Results at 4 weeks postinjection showed that treatment with 120 units incobotulinumtoxinA significantly improved dystonia, as measured by improvements from baseline in the 0- to 85-point Toronto Western Spasmodic Torticollis Rating Scale total score (Δ vs placebo, −7.5 points; 95% confidence interval [CI], −10.4 to −4.6 points; P < .001). The 240-Unit dose did not provide additional efficacy (Δ vs placebo, −9.0 points; 95% CI, −12.0 to −5.9 points; P < .001) and may be linked to an increased risk for adverse events.

For the second study, investigators enrolled 109 patients with benign essential blepharospasm who responded adequately to prior treatment with onabotulinumtoxinA administered at least 10 weeks earlier. Enrollees were randomly assigned in a 2:1 ratio to either a single treatment session similar to that most recently used (maximum, 50 units/eye) or placebo.

Results at 6 weeks postinjection showed that treatment with incobotulinumtoxinA (mean dose/injection site, 5.6 units; mean injections/eye, 6; mean dose/eye, 33.5 units) significantly improved dystonia, as evaluated using the change from baseline in the 0- to 4-point Jankovic Rating Scale Severity subscore (Δ vs placebo, −1.0 points; 95% CI, −1.4 to −0.5 points; P < .001).

Dosage and Administration

The recommended total dose for patients with cervical dystonia is 120 units incobotulinumtoxinA per treatment session, usually injected into the sternocleidomastoid, splenius capitis, levator scapulae, scalene, and/or the trapezius muscles. The dose, number, and location of injection sites should be based on the number/location of muscles involved, dystonia severity, and patient response to prior botulinum toxin injections.

For patients with blepharospasm, the dose, number, and location of incobotulinumtoxinA should be based on prior dosing with onabotulinumtoxinA. If the previous dose is unknown, the recommended starting dose is 1.25 to 2.5 units per injection site. In clinical trials, the mean dose per injection site was 5.6 units, the mean number of injections per eye was 6, and the mean dose per eye was 33.5 units. IncobotulinumtoxinA has not been studied for this indication in onabotulinumtoxinA-naive patients.

Adverse events most commonly reported with use of incobotulinumtoxinA in cervical dystonia included dysphagia (120 units, 13%, and 240 units, 18%, vs placebo, 3%), neck pain (7% and 15% vs 4%), muscle weakness (7% and 11% vs 1%), injection site pain (9% and 4% vs 7%), and musculoskeletal pain (7% and 4% vs 1%).

The FDA warns that patients with smaller neck muscle mass and those requiring bilateral injections into the sternocleidomastoid muscle may be at increased risk for dysphagia; limiting the dose may decrease this risk.

In patients with blepharospasm, ptosis (19% vs 9% for placebo), dry eye (16% vs 12%), and dry mouth (16% vs 3%) were most frequently observed. Other adverse events reported in more than 5% of patients at a rate higher than placebo included diarrhea, headache, visual impairment, dyspnea, nasopharyngitis, and respiratory tract infection.

The agency notes that injection of incobotulinumtoxinA into the orbicularis oculi muscle can lead to reduced blinking and corneal exposure with possible ulceration or perforation. Lower lid injections should not be repeated if diplopia occurs.

Potency units of incobotulinumtoxinA are not interchangeable with other botulinum toxin preparations and, as such, cannot be compared or converted into units for other products.

Contraindications to treatment include hypersensitivity to any botulinum toxin preparation or formulation components, and infection at the proposed injection site.

As with other botulinum toxin products, the safety labeling for incobotulinumtoxinA has a black box warning regarding the risk for distant spread of toxin effect that can cause botulism symptoms such as asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties.

These symptoms have been reported hours to weeks after injection; swallowing and breathing difficulties can be life-threatening, and fatalities have been reported.

Because of the risk for potentiation of toxin effects, caution is advised with concomitant use of aminoglycoside antibiotics or other agents that interfere with neuromuscular transmission such as curare-like compounds; anticholinergic effects may be increased by use of additional anticholinergic agents.

IncobotulinumtoxinA previously was approved in Canada for the symptomatic management of blepharospasm, cervical dystonia, and poststroke upper limb spasticity.