Pharmacology Update
Gabapentin Enacarbil Extended-Release Tablets (Horizant™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
A prodrug of gabapentin has been approved by the FDA for the treatment of restless legs syndrome (RLS). This is the first nondopaminergic drug approved for this indication. Gabapentin enacarbil is licensed from XenoPort, Inc., and marketed by GlaxoSmithKline as Horizant.
Indications
Gabapentin enacarbil is indicated for the treatment of moderate-to-severe primary RLS in adults.1
Dosage
The recommended dose is 600 mg once daily taken with food around 5 p.m.1 If the dose was not taken at the appropriate time, the next dose should be taken the following day. The tablet should be taken whole and not cut, crushed, or chewed.
Gabapentin enacarbil is available as 600 mg extended-release tablets.
Potential Advantages
Gabapentin enacarbil has a different side effects profile compared to dopaminergic drugs such as ropinirole and pramipexole. It has not been associated with rebound and augmentation.
Potential Disadvantages
The most frequently reported adverse effects (compared to placebo) were somnolence or sedation (20% vs 6%) and dizziness (13% vs 4%).1 As with antiepileptic drugs, gabapentin enacarbil may increase the risk of suicidal behavior and ideation.1 Patients should be monitored for this as well as emergence or worsening of depression and/or any changes in mood or behavior.
Comments
Gabapentin enacarbil provides improved absorption compared to gabapentin. Food further enhances the absorption. The efficacy and safety of gabapentin enacarbil was studied in two 12-week clinical trials in adults with RLS.1,2 The primary efficacy endpoints were the International Restless Legs Syndrome (IRLS) Rating Scale and Clinical Global Impression of Improvement (CGI-I) scores. The IRLS Rating Scale contains 10 items with a range of scores from 0 to 40 that assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence/sedation, and impact on activities of daily living and mood associated with RLS. CGI-I Scale is the investigators assessment of the patient's overall change in RLS symptoms from baseline. Those categorized as "much improved" or "very much improved" at 12 weeks are defined as responders. In Study 1, patients with IRLS of 15 or higher were randomized to 1200 mg of gabapentin enacarbil (n = 112) once daily at 5 p.m. or placebo (n = 108). In Study 2, they were randomized to 600 mg (n = 114), 1200 mg (n = 111), or placebo (n = 96). The mean changes in IRLS Scores in Study 1 were -13.2 for 1200 mg and -8.0 for placebo with response rates 76% and 39%, respectively. Results for Study 2 were -13.8 (600 mg), -13.0 (1200 mg), and -9.8 (placebo). The response rates were 73%, 77%, and 45%, respectively. The higher dose, 1200 mg, did not offer any added benefit over the 600 mg dose but was associated with a higher incidence of side effects. The most frequently reported adverse events were somnolence and dizziness. Efficacy was detected as early as week 1. Results from an open-label study indicate that the improvement was maintained for up to 64 weeks.3 There are currently no published comparative trials between gabapentin enacarbil and a dopaminergic agent. However, the magnitude of the changes in RLS scores was similar to those reported for ropinirole and pramipexole.4,5 Rebound and augmentation in RLS have not been reported with gabapentin. On the other hand, increased risk of suicidal behavior and ideation has been associated with gabapentin.
Clinical Implications
RLS is characterized by an urge to move the legs with or without an actual paresthesia, worsening of symptoms with inactivity, improvement with activity, and worsening of symptoms in the evening and at night.6 Currently, dopamineric agents (e.g., ropinirole, pramipexole) are FDA-approved treatments. With chronic therapy, patients may develop rebound or augmentation of their condition. Gabapentin provides an alternative that appears not to cause worsening of symptoms.
References
1. Horizant Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; April 2011.
2. Kushida CA, et al. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology 2009;72:439-446.
3. Ellenbogen AL, et al. A 52-week study of gabapentin enacarbil in restless legs syndrome. Clin Neuropharmacol 2011;34:8-16.
4. Miraplex Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; April 2011.
5. Requip Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; April 2009.
6. Satija P, Ondo WG. Restless legs syndrome: Pathophysiology, diagnosis and treatment. CNS Drugs 2008;22:497-518.
A prodrug of gabapentin has been approved by the FDA for the treatment of restless legs syndrome (RLS).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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