What is Horizant (gabapentin enacarbil)?

Horizant (Gabapentin Enacarbil): A First-Line Treatment for Restless Legs Syndrome

Horizant (gabapentin enacarbil) is a prodrug of gabapentin that is strongly recommended as a first-line treatment for adults with moderate to severe restless legs syndrome (RLS), with demonstrated efficacy in improving disease severity, sleep quality, and quality of life. 1

Mechanism and Formulation

Horizant is an extended-release prodrug of gabapentin that offers improved pharmacokinetics compared to regular gabapentin:

• Provides more predictable absorption and lower inter-patient variability in bioavailability than gabapentin 2
• FDA-approved specifically for moderate to severe primary RLS in adults 3
• First non-dopaminergic agent approved for RLS treatment 2

Efficacy for RLS Treatment

The American Academy of Sleep Medicine (AASM) gives gabapentin enacarbil a strong recommendation with moderate certainty of evidence for RLS treatment 1:

• Significantly improves disease severity, sleep quality, and quality of life with moderate effect size
• Demonstrated efficacy in multiple randomized controlled trials
• Effective regardless of disease severity, associated sleep disturbance, or prior dopamine agonist use 3
• Maintains effectiveness in longer-term treatment with lower relapse rates compared to placebo 3

Dosing Information

• FDA-approved dose: 600 mg once daily, taken with food at approximately 5 PM 4
• Higher doses (1200 mg) have been studied and may provide additional benefits for severe sleep disturbance associated with RLS, but with increased risk of side effects 5
• Titration is typically not required when starting at the 600 mg dose 4

Safety Profile and Side Effects

Common side effects include:

• Somnolence/sedation and dizziness (most common) 3
• Most adverse events are mild to moderate in severity 3
• Discontinuation rates in clinical trials were relatively low 3

Important safety advantages:

• No reports of augmentation (worsening of symptoms earlier in the day) - a significant advantage over dopaminergic medications 6
• No QT-interval prolongation reported 3

Clinical Considerations

Patient Selection

Horizant may be particularly beneficial for:

• Patients with moderate to severe primary RLS 1
• Those with RLS-associated sleep disturbances 5
• Patients with RLS symptoms associated with pain 2
• Those who have failed or experienced augmentation with dopamine agonists 3

Monitoring and Follow-up

• Regular assessment of treatment response using standardized scales (IRLS total score)
• Monitor for adverse effects, particularly somnolence and dizziness
• Dose adjustments may be needed in patients with renal impairment

Precautions

• Use caution in patients with renal impairment as gabapentin is primarily excreted unchanged by the kidneys 7
• Avoid abrupt discontinuation to prevent withdrawal symptoms
• Consider potential drug interactions, particularly with other CNS depressants
• Monitor for suicidal thoughts or behaviors (as with other antiepileptic medications) 8

Alternative Treatments for RLS

If Horizant is ineffective or not tolerated, other AASM-recommended options include:

• Gabapentin (strong recommendation) 1
• Pregabalin (strong recommendation) 1
• IV iron therapies for patients with appropriate iron status (ferritin ≤75 ng/mL or transferrin saturation <20%) 1
• Ferrous sulfate (conditional recommendation) 1
• Opioids like extended-release oxycodone (conditional recommendation, typically reserved for refractory cases) 1

Before initiating any pharmacological treatment for RLS, clinicians should address potential exacerbating factors such as alcohol, caffeine, antihistaminergic, serotonergic, and antidopaminergic medications, as well as untreated obstructive sleep apnea 1.