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. |
| Molecular Weight | 335.37 |
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 | Animal studies show developmental toxicity (neural tube defects, skeletal anomalies) at clinically relevant exposures. Human data limited; risk cannot be excluded. Avoid use in first trimester unless benefit outweighs risk. |
| 2nd trimester | May impair maternal folate metabolism; consider high-dose folate supplementation. Increased risk of fetal growth restriction with exposure in second and third trimesters. |
| 3rd trimester | Neonatal hemorrhage reported due to vitamin K deficiency; administer vitamin K to newborn. Risk of persistent pulmonary hypertension of the newborn (PPHN) with late exposure. |
Clinical note
Comprehensive clinical and safety monograph for XCOPRI (XCOPRI).
| Placental transfer | Placental transfer occurs; cord blood concentrations approximately 50-70% of maternal plasma levels. |
| Breastfeeding | Excreted in human milk in low concentrations. Infant serum levels are subtherapeutic; however, monitor infant for drowsiness, poor feeding, and weight gain. Consider risk of potential serious adverse reactions in nursing infants. |
■ 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 |
History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with cenobamate or other aromatic anticonvulsantsQTc interval shortening (familial short QT syndrome or baseline QTc <300 ms)Severe hepatic impairment (Child-Pugh Class C)
| 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. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase cenobamate levels. Take with or without food; consistency of administration with regard to meals is recommended. |
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| Lactation Rating | L3 (Moderately Safe) |
| 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. |
| 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. |
| Clinical Pearls | XCOPRI (cenobamate) requires a 2-week titration to minimize risk of serious hypersensitivity reactions including DRESS. It is a controlled substance (C-V) due to abuse potential. Monitor for QT prolongation, especially in patients with cardiac conditions or on other QT-prolonging drugs. Dosing adjustments needed for renal impairment (CrCl < 30 mL/min). Avoid abrupt discontinuation to prevent withdrawal seizures. |
| Patient Advice | Take exactly as prescribed; do not stop suddenly as it may cause increased seizures. · Report any rash, fever, or swollen lymph nodes immediately as these may be signs of a serious allergic reaction. · Avoid alcohol and grapefruit products while taking this medication. · May cause dizziness, double vision, or coordination problems; do not drive until you know how it affects you. · Use effective contraception because this drug may make birth control pills less effective. |