GABAPENTIN ENCARBIL
Clinical safety rating: safe
Antacids decrease absorption May cause somnolence dizziness and respiratory depression especially with opioids.
Gabapentin encarbil is a prodrug of gabapentin, which binds to the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system, reducing calcium influx and inhibiting neurotransmitter release.
| Metabolism | Gabapentin encarbil is rapidly hydrolyzed by non-specific esterases in the gastrointestinal tract to gabapentin. Gabapentin is not significantly metabolized and is excreted unchanged in urine. |
| Excretion | Renal: Gabapentin encarbil is a prodrug of gabapentin. Following absorption, it is rapidly hydrolyzed to gabapentin. Gabapentin is primarily excreted unchanged in urine via glomerular filtration. Approximately 80-90% of a dose is recovered in urine as gabapentin, with the remainder as metabolites and minor amounts (≤1%) in feces. Biliary excretion is negligible. |
| Half-life | The terminal elimination half-life of gabapentin derived from gabapentin encarbil is approximately 5-7 hours in patients with normal renal function. This half-life is prolonged in patients with renal impairment (up to 132 hours in anuria). Clinically, steady-state concentrations are achieved within 1-2 days. Twice-daily dosing is effective due to sustained exposure from the prodrug formulation. |
| Protein binding | Gabapentin is less than 3% bound to plasma proteins. The binding proteins are albumin and α1-acid glycoprotein, but the low binding indicates that protein binding interactions are not clinically relevant. |
| Volume of Distribution | The volume of distribution (Vd) of gabapentin is approximately 0.6-0.8 L/kg. This indicates distribution into total body water and some peripheral tissues. In patients with normal renal function, the Vd is not significantly altered, but in renal impairment, the Vd may decrease due to reduced tissue perfusion. |
| Bioavailability | Oral bioavailability of gabapentin from gabapentin encarbil is approximately 100% relative to gabapentin tablets. The prodrug is designed to be absorbed via monocarboxylate transporter type 1 (MCT-1) and sodium-dependent multivitamin transporter (SMVT) in the intestine, avoiding the saturable absorption of gabapentin. Thus, bioavailability is high and dose-proportional over the therapeutic range. |
| Onset of Action | Oral administration: Time to peak plasma concentration (Tmax) of gabapentin is approximately 1 hour (range 0.5-3 hours) following gabapentin encarbil. Clinical onset for analgesic effect (e.g., postherpetic neuralgia) may be observed within the first week of therapy, but maximum effect may require 2-4 weeks. |
| Duration of Action | Duration of action for pain relief is approximately 12 hours, supporting twice-daily dosing. The extended pharmacodynamic effect is related to gabapentin's binding to the α2δ subunit of voltage-gated calcium channels, which modulates neurotransmitter release. Clinically, dosing is every 12 hours for pain indications. |
| Molecular Weight | 521.6 |
Oral gabapentin encarbil 600 mg once daily with evening meal, titrated based on response and tolerability, maximum 1200 mg once daily. Alternatively, 600 mg twice daily may be used; maximum 2400 mg/day.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | For CrCl ≥60 mL/min: no adjustment. CrCl 30-59: 600 mg once daily; CrCl 15-29: 300 mg once daily; CrCl <15: not recommended; hemodialysis: 300 mg after each dialysis session. |
| Liver impairment | No dose adjustment recommended for mild to moderate hepatic impairment (Child-Pugh A or B). Not studied in severe impairment (Child-Pugh C); use with caution. |
| Pediatric use | Approved for partial-onset seizures in patients ≥3 years: starting dose 10-15 mg/kg/day divided 3 times daily, titrate to effective dose (usual range 25-50 mg/kg/day, max 60 mg/kg/day). For gabapentin encarbil, pediatric dosing not established. |
| Geriatric use | Initiate at lower end of dosing range due to age-related renal function decline. Monitor for sedation, dizziness, and falls. Adjust based on creatinine clearance. |
| 1st trimester | Risk cannot be ruled out; animal studies have shown fetal developmental abnormalities including skeletal and renal defects. Human data limited. |
| 2nd trimester | Use if benefit outweighs risk; may be associated with major congenital malformations (e.g., cardiac defects) from first-trimester exposure. |
| 3rd trimester | Avoid in third trimester due to risk of neonatal withdrawal (jitteriness, hypotonia, respiratory depression) and possible reduced efficacy. |
Clinical note
Antacids decrease absorption May cause somnolence dizziness and respiratory depression especially with opioids.
| FDA category | Animal |
| Placental transfer | Crosses placenta; gabapentin levels in cord blood are similar to maternal plasma levels (ratio 1.0-2.0). |
| Breastfeeding |
■ FDA Black Box Warning
No FDA black box warning.
| Common Effects | neuropathic pain |
| Serious Effects |
History of hypersensitivity to gabapentin, gabapentin enacarbil, or any component of the formulation
| Precautions | May cause dizziness, somnolence, and syncope; caution with concomitant CNS depressants, Renal impairment may alter drug clearance; dose adjustment required, Potential for abuse and dependence; monitor for signs of misuse, Serious skin reactions (e.g., DRESS, Stevens-Johnson syndrome) reported |
| Food/Dietary | No significant food interactions. Gabapentin encarbil can be taken with or without food. Avoid alcohol as it may increase sedation and risk of dizziness. |
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| Gabapentin enacarbil is a prodrug of gabapentin; gabapentin is excreted into breast milk in low amounts. Infant serum levels are 2-9% of maternal level. Monitor infant for drowsiness, poor feeding, and adequate weight gain. Consider risk-benefit for preterm or neonates with renal impairment. |
| Lactation Rating | L2 (Probably Compatible) |
| Teratogenic Risk | Gabapentin encarbil is a prodrug of gabapentin. Data on gabapentin use in pregnancy are limited but do not suggest a major teratogenic risk. However, gabapentin has been associated with a small increased risk of major congenital malformations, particularly cardiac defects, based on some observational studies. First trimester exposure may be associated with a relative risk of approximately 1.2 for major malformations. Third trimester exposure may increase the risk of neonatal withdrawal symptoms (e.g., irritability, feeding difficulties) and poor neurodevelopmental outcomes. The risk is lower than for antiepileptic drugs like valproate, but caution is advised. |
| Fetal Monitoring | Monitor maternal renal function, serum gabapentin levels if dose adjustment needed, and clinical response. For fetal monitoring: regular ultrasound surveillance for growth and development, especially if used in combination with other antiepileptic drugs. Newborns should be monitored for withdrawal symptoms (irritability, jitteriness, feeding difficulties) and respiratory depression, particularly after third trimester exposure. |
| Fertility Effects | Animal studies have not shown significant effects on fertility. In humans, gabapentin is not known to impair male or female fertility. However, as with any medication used for chronic conditions, individual variations may occur but no specific effect on reproductive function has been established. |
| Clinical Pearls | Gabapentin encarbil is a prodrug of gabapentin with improved bioavailability (~65% vs 30-60% for gabapentin). No food effect on absorption; can be taken without regard to meals. Dosing is twice daily (not three times daily) due to extended-release profile. Monitor renal function; dose adjustment required for CrCl <60 mL/min. Taper when discontinuing to avoid withdrawal symptoms. Not interchangeable with immediate-release gabapentin on a mg-per-mg basis. Onset of action for restless legs syndrome may take up to 2 weeks. Avoid use in patients with history of substance abuse due to potential for euphoria. |
| Patient Advice | Take exactly as prescribed, usually twice daily. · Do not chew or crush the extended-release tablets. · You may take with or without food. · Do not stop suddenly; taper under medical supervision. · Dizziness and drowsiness are common; avoid driving until you know how it affects you. · Notify doctor if you have kidney problems, require dose adjustment. · Report any suicidal thoughts or unusual mood changes immediately. · Keep tablets in original container, protect from moisture. |