Gabapentin Enacarbil Dosing for Restless Legs Syndrome
For adults with moderate to severe RLS and normal renal function, initiate gabapentin enacarbil at 600 mg once daily at approximately 5 PM with food, and consider increasing to 1200 mg once daily if symptoms—particularly severe sleep disturbances—are not adequately controlled. 1
Standard Dosing Regimen
Start with 600 mg once daily taken at approximately 5 PM with food as the FDA-approved initial dose, which significantly improves RLS symptoms and has a favorable adverse event profile 2, 3
The 1200 mg once daily dose is the most validated treatment for both subjective RLS symptoms and severe sleep disturbances associated with RLS, showing superior efficacy in clinical trials despite FDA approval being limited to 600 mg 2, 4
Avoid intermediate doses (e.g., 900 mg) as Japanese dose-finding studies demonstrated that half-landing doses between 600 mg and 1200 mg failed to show significant improvement and caused more early discontinuations due to adverse effects 2
Timing and Administration
Administer once daily at approximately 5 PM with food to optimize absorption and align with the evening/nighttime worsening of RLS symptoms 4, 5
The extended-release formulation provides dose-proportional exposure without saturation, unlike immediate-release gabapentin 6
Dose Selection Strategy
Use 600 mg daily for treating primarily subjective RLS symptoms in patients with moderate disease severity 2, 3
Escalate to 1200 mg daily for patients with severe RLS (baseline IRLS score ≥24) or significant sleep disturbances, as this dose demonstrated superior improvements in IRLS total scores (treatment difference of -18.0 vs placebo compared to -16.3 for 600 mg) and higher CGI-I responder rates (74% vs 64%) 3
Both doses showed significant efficacy at 12 weeks, with the 1200 mg dose providing additional benefits for sleep, mood, quality of life, and pain outcomes 3, 4
Expected Efficacy Timeline
Symptom improvement occurs within days to weeks, with significant improvements in IRLS total scores and CGI-I response rates evident by week 12 3, 5, 6
Long-term efficacy is sustained, with maintenance of response demonstrated in 52-week extension studies and lower relapse rates compared to placebo in 36-week maintenance trials 4, 5
Common Adverse Events and Monitoring
Somnolence/sedation (21-24%) and dizziness (14-19%) are the most frequent adverse events, typically mild to moderate in severity and transient 3, 4, 5
These adverse events are more common than placebo (somnolence 3%, dizziness 3%) but rarely lead to discontinuation 3
No reports of augmentation or QT-interval prolongation have been documented, a critical advantage over dopaminergic agents 4
Critical Advantages Over Dopamine Agonists
Gabapentin enacarbil is strongly recommended as first-line therapy by the American Academy of Sleep Medicine with moderate certainty of evidence, replacing dopamine agonists which are now recommended against due to augmentation risk 1, 7
Unlike dopamine agonists (pramipexole, ropinirole, rotigotine), gabapentin enacarbil does not cause augmentation—the paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread 1, 7
Renal Dosing Considerations
- For patients with end-stage renal disease, switch to immediate-release gabapentin starting at 100 mg post-dialysis or at bedtime, with maximum doses of 200-300 mg daily, as gabapentin enacarbil dosing in severe renal impairment is not well-established 8
Adjunctive Iron Therapy
- Check morning fasting ferritin and transferrin saturation before or concurrent with initiating gabapentin enacarbil, and supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20%, as iron repletion can significantly enhance RLS symptom control independent of gabapentin enacarbil 1