FDA Approves New Gabapentin Formulation for RLS

Emma Hitt, PhD

April 11, 2011

April 11, 2011 (UDDATED April 28, 2011) — The US Food and Drug Administration (FDA) has approved gabapentin enacarbil extended-release tablets (Horizant; GlaxoSmithKline and XenoPort Inc) for the treatment of moderate to severe primary restless legs syndrome (RLS) in adults.

Gabapentin is the first medication in its class to be approved for the treatment of moderate to severe primary RLS, a statement from the company notes. The drug's efficacy in the treatment of moderate to severe primary RLS was confirmed in two 12-week clinical trials in adults.

"Our experience has shown that patients with moderate-to-severe primary RLS can suffer from a range of disruptive symptoms and may benefit from a new treatment option," said Richard K. Bogan, MD, chairman and chief medical officer of SleepMed of South Carolina in Columbia, a clinical trial investigator, in the company release.

Gabapentin enacarbil extended-release tablets are absorbed via the body's nutrient transport mechanisms. The drug is then converted into gabapentin, which binds to a specific type of calcium channel receptor, with no known affinity for other receptors. However, the exact mechanism of action of this agent in treating RLS is unknown.

Gabapentin enacarbil extended-release tablets are not interchangeable with other forms of gabapentin because of differing pharmacokinetics. The same doses of this and other gabapentin products result in different plasma concentrations of gabapentin.

The newly approved drug may cause significant driving impairment, the statement notes. In three 12-week clinical trials, the 2 most commonly observed adverse reactions for the 600 mg per day (n = 163) and 1200 mg per day (n = 269) doses were lethargy (20%, 27%) and dizziness (13%, 22%), compared with 6% and 4%, respectively, with placebo (n = 245).

The recommended dosage is 600 mg once daily taken with food at approximately 5:00 PM. In addition, the new formulation is contraindicated for patients who need to sleep during the day and remain awake at night. If the dose is not taken at the recommended time, the next dose should be taken the following day as prescribed. The tablets should be swallowed whole and not cut, crushed, or chewed.

Gabapentin is an antiepileptic drug. This class of drugs has been associated with an increased risk for suicidal thoughts, depression, and mood changes.

The prevalence for RLS in adults with medically significant symptoms ranges from 1.5% to 2.7% in the United States and/or Western Europe. Diagnostic criteria for RLS include an urge to move the legs usually accompanied or caused by uncomfortable leg sensations, symptoms begin or worsen during periods of inactivity and are partially or totally relieved by movement at least as long as the activity continues, and symptoms are worse or occur only in the evening or night. Potential genetic variants of RLS may exist.

Use in Specific Populations

Gabapentin enacarbil is classified as Pregnancy Category C and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Although there are no adequate, well-controlled studies in pregnant women, animal studies suggest that the drug is developmentally toxic when given to pregnant animals at doses and exposures exceeding those used clinically. During labor and delivery, the clinical effect is unknown.

It is not specifically known whether gabapentin derived from the enacarbil compound is secreted in human milk, but oral administration of gabapentin products is followed by secretion of gabapentin into human milk. Considering the importance of the drug to the mother as well as the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue maternal use of gabapentin enacarbil.

The safety and efficacy of gabapentin enacarbil has not been studied in pediatric patients. Of 515 patients treated with gabapentin enacarbil in the 3 double-blind, placebo-controlled, 12-week clinical trials for RLS, 11% were 65 to 74 years old and 1% were 75 years or older. The number of patients at least 65 years old was insufficient to determine whether this age group responds differently than younger individuals.

In patients with impaired renal function, the risk for adverse reactions may be increased, because gabapentin is known to be almost exclusively excreted by the kidney. In particular, elderly patients are more likely to have reduced renal function and may therefore require adjustment in the frequency of dosing based on calculated creatinine clearance (CrCl). In patients with a CrCl of 30 to 59 mL/minute, 600 mg of gabapentin enacarbil should be administered on day 1, day 3, and everyday thereafter. Because the dose of gabapentin enacarbil cannot be reduced below 600 mg, it is not recommended for use in patients with a CrCl of less than 30 mL/minute or in patients receiving hemodialysis.

More information on gabapentin enacarbil is available on this particular FDA Web site.

Laurie Barclay, MD, contributed to this news article.