FDA Approves Botox for Upper Limb Spasticity

Yael Waknine

March 10, 2010

March 10, 2010 ( UPDATED March 17, 2010) — The US Food and Drug Administration (FDA) has approved a new indication for onabotulinumtoxin A injection (Botox; Allergan, Inc) for upper limb spasticity. This condition commonly occurs in the flexor muscles of the elbow, wrist, and fingers for adults with conditions such as stroke, traumatic brain injury, cerebral palsy, or progressive multiple sclerosis.

The drug is derived from Clostridium botulinum and serves to inhibit acetylcholine release, leading to a temporary paralysis of the spastic muscle.

In an FDA news release, Russell Katz, MD, director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research said: "Muscles affected by spasticity have increased stiffness and tightness, which may lead to pain, difficulties with hygiene and other activities of daily living, and may affect how a patient looks," said. "In clinical trials, treatment with Botox was found to be beneficial to patients with upper limb spasticity."

"Upper limb spasticity can manifest weeks, months or even years after the original injury, possibly after a patient has stopped seeing a neurologist, physiatrist or their rehabilitation specialist, which is why it is severely undertreated and there's a low awareness of the condition," said Mitchell F. Brin, MD, Allergan's senior vice president of global development and chief scientific officer, Botox, in a company news release.

Clinical Trials Support Drug Approval

FDA approval was based on data from 3 double-blind, placebo-controlled clinical studies of patients at least 6 weeks after a stroke with significantly increased upper limb muscle tone, as evaluated with use of the Ashworth scale, a globally accepted measure ranging from passive movement (1) to limb rigid in flexion or extension (4).

The first study (n = 126) showed that onabotulinumtoxin A at doses ranging from 200 to 240 units yielded statistically significant decreases from baseline in both wrist and finger flexor tone relative to placebo at 6 weeks as measured with use of the Ashworth scale (–2.0 and –1.0, respectively; P < .05).

These findings were supported by a second study of 91 patients, showing that a 360-unit dose of onabotulinumtoxin A yielded a statistically significant reduction from baseline in wrist flexor tone at 6 weeks relative to placebo (–1.5; P < .05).

In the third study (n = 88), patients receiving a 360-unit dose of onabotulinumtoxin A achieved significant decreases in wrist, finger, and elbow flexor tone at week 4 (–1.5, –1.0, and –1.0, respectively; P < .05).

Onabotulinumtoxin A doses should be selected based on muscles affected, severity of muscle activity, prior response to treatment, and adverse event history. In clinical trials, doses ranging from 75 to 360 units were divided among selected muscles at a given treatment session.

The recommended dose for the biceps brachii is 100 to 200 units over 4 sites; for the flexor carpi radialis/ulnaris muscles, 12.5 to 50 units should be given in 1 site; and for the flexor digitorum profundis/sublimes, 30 to 50 units should be administered in 1 site. Treatments should be spaced at least 12 weeks apart.

Onabotulinumtoxin A Should Not Replace Rehabilitation

FDA officials note that the product is not intended as a substitute for physical therapy and other rehabilitative care. Also, efficacy has not been demonstrated in treating muscle spasms of other upper limb muscles or the legs or in patients with fixed contracture.

Adverse Events

Adverse events most commonly reported with use of onabotulinumtoxin A in spasticity trials occurred in less than 7% of patients and included nausea, fatigue, bronchitis, muscle weakness, and arm pain.

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

The FDA last year implemented a boxed warning for the product regarding the risk of spreading of botulinum toxin from the injection site to other parts of the body, causing 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.

Onabotulinumtoxin A previously was approved for the treatment of severe primary axillary hyperhidrosis, blepharospasm, strabismus, cervical dystonia, and cosmetic purposes.