HORIZANT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for HORIZANT (HORIZANT).
Gabapentin enacarbil is a prodrug of gabapentin, which binds to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, reducing the release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P. This modulation decreases neuronal excitability and pain signaling.
| Metabolism | Hydrolyzed by non-specific esterases (primarily in enterocytes and hepatocytes) to gabapentin; gabapentin is not significantly metabolized and is excreted renally unchanged. Minor metabolism via gabapentin lactam formation. |
| Excretion | Renal: 90-95% unchanged in urine. Fecal/biliary: minimal (≤3%). |
| Half-life | 5-7 hours; in patients with CrCl <30 mL/min, half-life is prolonged with clinical need for dose adjustment. |
| Protein binding | ≤3%, primarily albumin. |
| Volume of Distribution | 0.9-1.3 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral: 90-100% (well absorbed, minimal first-pass effect). |
| Onset of Action | Oral: 1-2 hours; peak effects at 3-4 hours. |
| Duration of Action | 4-6 hours; clinical duration may be extended in renal impairment. |
| Molecular Weight | 249.27 |
600 mg orally once daily, taken in the morning with or without food.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | For CrCl 30-59 mL/min: 300 mg once daily; for CrCl 15-29 mL/min: 300 mg every other day; for CrCl <15 mL/min or on hemodialysis: not recommended. |
| Liver impairment | No dose adjustment required for mild-to-moderate hepatic impairment (Child-Pugh A or B); not studied in severe impairment (Child-Pugh C). |
| Pediatric use | Not approved for use in pediatric patients under 18 years of age. |
| Geriatric use | Select dose based on renal function; monitor for dizziness, somnolence, and falls; consider lower starting dose if renal impairment exists. |
| 1st trimester | Avoid. Animal studies show teratogenicity; no adequate human data. |
| 2nd trimester | Avoid. May cause fetal harm; use only if benefit outweighs risk. |
| 3rd trimester | Avoid. Risk of neonatal withdrawal and respiratory depression. |
Clinical note
Comprehensive clinical and safety monograph for HORIZANT (HORIZANT).
| Placental transfer | Crosses placenta in animal studies; expected in humans due to low molecular weight. |
| Breastfeeding | Excreted in breast milk; potential for adverse effects in infant. Manufacturer recommends discontinuing drug or breastfeeding. |
| Lactation Rating | L4 (Possibly Hazardous) |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to gabapentin or any componentSevere renal impairment (CrCl <30 mL/min) if not dialyzed
| Precautions | Central nervous system depression (dizziness, somnolence), syncope, suicidal behavior and ideation, respiratory depression (especially with concomitant CNS depressants or in patients with respiratory compromise), hypersensitivity reactions (including drug reaction with eosinophilia and systemic symptoms), increased seizure frequency if withdrawn abruptly, driving impairment, renal impairment (dose adjustment required), and carcinogenicity (pancreatic acinar cell tumors in animal studies; clinical significance unknown). |
| Food/Dietary | Administration with food (especially high-fat meals) increases the bioavailability and peak concentration of gabapentin enacarbil. It is recommended to take consistently with food to maintain stable drug levels. There are no specific dietary restrictions, but high-fat meals may enhance absorption. Avoid alcohol as it may potentiate CNS depressant effects. |
Loading safety data…
| Teratogenic Risk | Pregnancy Category C. In animal studies, gabapentin enacarbil (active ingredient of HORIZANT) caused developmental toxicity including skeletal malformations and reduced fetal weight at doses similar to human exposure. There are no adequate and well-controlled studies in pregnant women. First trimester: Potential risk based on animal data; second and third trimesters: Unknown risk; use only if maternal benefit outweighs fetal risk. |
| Fetal Monitoring | Monitor maternal renal function, blood pressure, and signs of CNS depression. Fetal monitoring includes ultrasound for growth and development if exposure occurs during pregnancy. No specific fetal monitoring recommended beyond standard obstetric care. |
| Fertility Effects | In animal studies, no adverse effects on fertility were observed at doses up to 3 times the maximum human dose. No human data available; potential effect on male or female fertility is unknown. |
| Clinical Pearls | HORIZANT (gabapentin enacarbil) is a prodrug of gabapentin, designed for extended-release oral administration. It is approved for moderate-to-severe primary restless legs syndrome (RLS) and postherpetic neuralgia (PHN). Due to its extended-release formulation, it should not be substituted with immediate-release gabapentin on a milligram-per-milligram basis. Dose adjustment is required in renal impairment; creatinine clearance (CrCl) <30 mL/min is a contraindication for RLS. For PHN, starting dose is 600 mg once daily, titrated to 1200 mg once daily as tolerated. Administer with food to enhance absorption. Avoid abrupt discontinuation to prevent withdrawal symptoms. Monitor for CNS depression, dizziness, somnolence, and suicidal behavior or ideation. |
| Patient Advice | Take exactly as prescribed; do not crush, chew, or split the tablets as they are extended-release. · Take with food to improve absorption and reduce stomach upset. · Do not drive or operate heavy machinery until you know how HORIZANT affects you, as it may cause dizziness and drowsiness. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they may increase sedation. · Do not stop taking suddenly; tapering is required under medical supervision to avoid withdrawal symptoms. · Report any new or worsening depression, suicidal thoughts, or unusual changes in mood or behavior. · Swallow tablets whole with a full glass of water; do not cut or break. · Keep tablets in original container; protect from moisture and heat. |