Gabapentin Enacarbil Dosing for Restless Legs Syndrome

The FDA-approved dose of gabapentin enacarbil for RLS is 600 mg once daily, taken at approximately 5 PM with food. 1, 2

Standard Dosing Protocol

Administer 600 mg once daily at 5 PM with food - this is the only FDA-approved dose, as higher doses were not considered to provide additional benefits and were associated with increased rates of somnolence and dizziness 3, 4
No titration is required - gabapentin enacarbil can be initiated directly at 600 mg without dose escalation 4, 5
The extended-release formulation provides sustained gabapentin exposure with a time to peak concentration of 7-9 hours and elimination half-life of approximately 6 hours 5

Integrated analysis of three 12-week trials demonstrated that gabapentin enacarbil 600 mg significantly improved International Restless Legs Scale (IRLS) scores compared to placebo (adjusted mean treatment difference: -4.3 points, p<0.0001) 4
70.2% of patients on 600 mg were rated as "much" or "very much improved" on the Clinical Global Impression-Improvement scale versus 42.2% on placebo (adjusted odds ratio 3.1, p<0.0001) 4
The 600 mg dose showed similar efficacy to higher doses (1200 mg, 1800 mg, 2400 mg) for subjective RLS symptoms, but with a more favorable side effect profile 3, 4

While 600 mg is the FDA-approved dose, clinical trial data suggests nuanced considerations:

1200 mg once daily may be more effective for patients with severe sleep disturbance associated with RLS, though this is not FDA-approved 3, 6
The 1200 mg dose maintained improvements in RLS symptoms over 52-64 weeks of treatment with 84.8% of patients achieving responder status 6, 7
Avoid intermediate doses like 900 mg - a Japanese dose-finding study showed this dose failed to demonstrate significant IRLS improvement and caused higher early discontinuation rates 3
If considering doses above 600 mg, the dose-response relationship for adverse events (particularly somnolence and dizziness) becomes more pronounced 4, 5

Timing is essential - the 5 PM administration targets symptom onset, which typically worsens in the evening and at night 4, 5
Food requirement - gabapentin enacarbil must be taken with food to ensure proper absorption and pharmacokinetic profile 4, 5
Monitor for common adverse effects: somnolence (19.7%) and dizziness (11.5%) are most frequent, typically mild to moderate in intensity 6
Long-term safety profile is favorable - 52-week studies showed no clinically relevant changes in vital signs, laboratory parameters, or electrocardiograms 6

Renal impairment requires dose adjustment - gabapentin enacarbil is renally eliminated, though specific dosing for RLS in renal disease is not well-established in the literature provided 8
Pregnancy considerations - the American Academy of Sleep Medicine recommends considering pregnancy-specific safety profiles when treating RLS in pregnant women 1

Before initiating gabapentin enacarbil:

Check iron studies (morning fasting ferritin and transferrin saturation after avoiding iron supplements for 24 hours) - if ferritin ≤75 ng/mL or transferrin saturation <20%, address iron deficiency first or concurrently 1, 2
Review and discontinue exacerbating medications including antihistamines, serotonergic agents, antidopaminergics, alcohol, and caffeine 1, 2
Screen for untreated obstructive sleep apnea, as this can worsen RLS symptoms 1, 2

Gabapentin enacarbil does not cause augmentation - the paradoxical worsening of RLS symptoms seen with long-term dopamine agonist use (pramipexole, ropinirole, rotigotine) 2, 9
The American Academy of Sleep Medicine now strongly recommends alpha-2-delta ligands (including gabapentin enacarbil) as first-line therapy over dopaminergic agents 1, 2