XCOPRI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for XCOPRI (XCOPRI).
XCOPRI (cenobamate) is a tetrazole derivative anticonvulsant that reduces neuronal excitability through inhibition of voltage-gated sodium channels (persistent sodium current) and positive allosteric modulation of GABA-A receptors.
| Metabolism | Primarily metabolized by glucuronidation via UGT2B7 and UGT2B4, with minor contribution from CYP2E1; also undergoes O-glucuronidation. No significant metabolism by other CYP enzymes. |
| Excretion | Primarily renal, with approximately 70% of the dose excreted as unchanged drug in urine and 30% as inactive metabolites. Fecal elimination accounts for <2%. |
| Half-life | 50-70 hours, allowing once-daily dosing. Steady-state is reached in approximately 2 weeks. |
| Protein binding | 99.5% bound to human serum albumin. |
| Volume of Distribution | 0.1 L/kg, indicating extensive confinement to the vascular compartment. |
| Bioavailability | 100% (oral solution); tablet bioavailability is 92% relative to oral solution. |
| Onset of Action | Not applicable for seizure prophylaxis; therapeutic effect develops over days to weeks. |
| Duration of Action | 24 hours due to once-daily dosing, maintained by dose titration. |
Oral, 100 mg once daily for 2 weeks, then increase to 200 mg once daily. Maximum dose 400 mg once daily.
| Dosage form | TABLET |
| Renal impairment | GFR 30-89 mL/min: No adjustment. GFR 15-29 mL/min: 50 mg once daily for 2 weeks, then 100 mg once daily; maximum 200 mg once daily. GFR <15 mL/min or dialysis: Not recommended. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: 50 mg once daily for 2 weeks, then 100 mg once daily; maximum 200 mg once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Not approved for patients <18 years. No established pediatric dosing. |
| Geriatric use | No specific dose adjustment based on age alone. Monitor renal function and consider starting at lower dose (50 mg once daily) due to age-related renal decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for XCOPRI (XCOPRI).
| Breastfeeding | It is not known whether cenobamate is excreted in human milk. The M/P ratio is unknown. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. |
| Teratogenic Risk | XCOPRI (cenobamate) is classified as Pregnancy Category C. In animal studies, cenobamate was associated with developmental toxicity including increased fetal mortality and reduced fetal body weight. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Fetal risks may occur throughout pregnancy, but the highest risk for major malformations is during the first trimester. During the second and third trimesters, exposure may be associated with adverse effects on fetal growth and neurodevelopment. |
■ FDA Black Box Warning
Risk of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, which can be fatal or life-threatening. Discontinue at first sign of rash or other signs of hypersensitivity.
| Serious Effects |
Known hypersensitivity to cenobamate or any component; familial short QT syndrome; concurrent use with CYP2C8 substrates (e.g., repaglinide) due to risk of hypoglycemia from decreased repaglinide metabolism (cenobamate is a moderate CYP2C8 inhibitor).
| Precautions | DRESS/multiorgan hypersensitivity, QT shortening (contraindicated with familial short QT syndrome), suicidal behavior and ideation, neurological adverse reactions (somnolence, dizziness, gait disturbance), hepatotoxicity, and withdrawal seizures upon abrupt discontinuation. |
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| Fetal Monitoring | Pregnant women receiving XCOPRI should be monitored with regular prenatal care including ultrasound to assess fetal growth and anatomy. Additionally, monitor for withdrawal symptoms in the neonate after delivery, as antenatal exposure to cenobamate may cause neonatal sedation or withdrawal. Consider monitoring of maternal serum drug levels if available, though specific therapeutic ranges are not established. |
| Fertility Effects | No human data are available regarding the effect of cenobamate on fertility. In animal studies, cenobamate did not impair fertility in male or female rats at clinically relevant doses. However, limited data suggest possible effects on spermatogenesis in some species, so the potential for human fertility impairment cannot be ruled out. |