What is the recommended use and dosage of Horizant (gabapentin enacarbil)?

Horizant (Gabapentin Enacarbil): Recommended Use and Dosage

Primary Indication

Horizant (gabapentin enacarbil) is FDA-approved for the treatment of moderate to severe primary restless legs syndrome (RLS) in adults, with a recommended dose of 600 mg once daily taken at approximately 5 PM with food. 1

Dosing Regimen

Standard Dosing for RLS

• Administer 600 mg once daily at approximately 5 PM with food 1, 2
• This is the FDA-approved dose based on optimal benefit-to-risk ratio 3, 4
• No titration is required—start directly at 600 mg 1

Alternative Dosing Considerations

• While the FDA approved only 600 mg/day, clinical trials evaluated doses up to 1200 mg/day 3, 5
• The 1200 mg dose showed additional benefits for severe sleep disturbances associated with RLS but carries higher rates of somnolence and dizziness 3
• Doses higher than 600 mg were not FDA-approved because the additional benefit did not justify the increased adverse event risk 3, 4

Clinical Efficacy Evidence

Symptom Improvement

• Gabapentin enacarbil 600 mg significantly improved RLS symptoms compared to placebo, with 70.2% of patients rated as "much" or "very much" improved versus 42.2% on placebo 5
• Mean improvement in International Restless Legs Scale (IRLS) total score was -13.6 points versus -9.3 for placebo (treatment difference -4.3 points, p<0.0001) 5
• The American Academy of Sleep Medicine gives gabapentin enacarbil a strong recommendation for use in adults with RLS, based on moderate certainty of evidence 6

Long-Term Safety and Efficacy

• Efficacy is sustained for up to 64 weeks of continuous treatment 7, 4
• In a 52-week extension study, 84.8% of subjects maintained "much improved" or "very much improved" status 7

Adverse Effects Profile

Most Common Adverse Events

• Somnolence (19.7%) and dizziness (11.5%) are the most frequently reported adverse events 7
• Most adverse events are mild to moderate in severity 2, 7
• Treatment discontinuation due to adverse events occurs in approximately 10% of patients 7

Notable Safety Advantages

• No reports of augmentation (worsening of RLS symptoms with chronic dopamine agonist use) 2
• No QT-interval prolongation reported 2
• No clinically relevant changes in vital signs, laboratory parameters, or electrocardiograms 7

Renal Dosing Adjustments

Gabapentin enacarbil requires dose adjustment in renal impairment, though specific dosing recommendations for the extended-release formulation differ from immediate-release gabapentin 1

• Creatinine clearance should be assessed before initiating therapy 1
• Patients with severe renal impairment (CrCl <30 mL/min) or on hemodialysis may require dose reduction or alternative therapy 1

Critical Prescribing Considerations

Administration Guidelines

• Must be taken with food to optimize absorption 1
• Tablets should be swallowed whole—do not crush, chew, or split 1
• Timing at 5 PM is recommended to align peak drug levels with typical RLS symptom onset in the evening 1, 5

Discontinuation Protocol

• Taper gradually over a minimum of 1 week if discontinuing 1
• Abrupt discontinuation should be avoided 1

Drug-Specific Warnings

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported and can be fatal 1
• Monitor for fever, rash, lymphadenopathy, and organ system involvement 1
• Contraindicated in patients with hypersensitivity to gabapentin or gabapentin enacarbil 1

Guideline-Based Positioning

The American Academy of Sleep Medicine ranks gabapentin enacarbil as the #1 recommended pharmacologic treatment for RLS (ahead of gabapentin and pregabalin), with a strong recommendation 6

This positioning reflects:

• Moderate certainty of evidence for efficacy 6
• Clinically significant improvements in disease severity, sleep quality, and quality of life 6
• Favorable safety profile compared to dopamine agonists (no augmentation risk) 2

Common Pitfalls to Avoid

• Do not use doses higher than 600 mg without clear justification—the FDA determined that higher doses provide minimal additional benefit with increased adverse events 3, 4
• Do not administer without food—absorption is significantly reduced in fasting states 1
• Do not confuse with immediate-release gabapentin dosing—gabapentin enacarbil is dosed once daily, not three times daily 1
• Do not overlook renal function assessment—gabapentin enacarbil is renally excreted and requires dose adjustment in renal impairment 1