LEVETIRACETAM
Clinical safety rating: safe
No significant drug interactions May cause behavioral abnormalities including psychosis and aggression.
Levetiracetam's precise mechanism of action is unknown. It binds to synaptic vesicle protein 2A (SV2A), which may modulate neurotransmitter release and reduce neuronal excitability. It also inhibits N-type calcium channels and reduces calcium influx, contributing to antiepileptic effects.
| Metabolism | Levetiracetam is not extensively metabolized in the liver. Approximately 24% undergoes enzymatic hydrolysis via amidase enzymes (not CYP450) to an inactive carboxylic acid metabolite. The main metabolic pathway is hydrolysis of the acetamide group. |
| Excretion | Primarily renal (66% unchanged, 27% as inactive metabolite); minimal fecal (<2%). |
| Half-life | 6–8 hours in adults; prolonged to 10–11 hours in mild-to-moderate renal impairment (CrCl 30–50 mL/min) and 16–24 hours in severe impairment (CrCl <30 mL/min); neonates up to 16 hours. |
| Protein binding | <10%; primarily albumin. |
| Volume of Distribution | 0.5–0.7 L/kg; approximates total body water; distributes into CSF effectively. |
| Bioavailability | Oral: 100% (well absorbed); IV: 100%. |
| Onset of Action | Oral: 1–2 hours (peak plasma); IV: immediate (within minutes) after infusion. |
| Duration of Action | About 8–12 hours; requires twice-daily dosing; extended half-life in renal impairment may allow once-daily dosing. |
| Molecular Weight | 170.21 |
500-1500 mg PO/IV BID; initial 500 mg BID, titrate by 500 mg BID every 2 weeks as tolerated; maximum 3000 mg/day.
| Dosage form | TABLET |
| Renal impairment | CrCl >80 mL/min: 500-1500 mg BID; CrCl 50-80: 500-1000 mg BID; CrCl 30-50: 250-750 mg BID; CrCl <30: 250-500 mg BID; ESRD on dialysis: 500-1000 mg once daily with 250-500 mg supplemental dose after dialysis. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce maintenance dose by 50%; Child-Pugh C: reduce maintenance dose by 50%. |
| Pediatric use | 1 month to <6 months: 7 mg/kg BID, titrate to 21 mg/kg BID; 6 months to <4 years: 10 mg/kg BID, titrate to 25 mg/kg BID; 4 to <16 years: 10 mg/kg BID, titrate to 30 mg/kg BID; maximum 60 mg/kg/day. |
| Geriatric use | Initiate at lower dose (250-500 mg BID) due to age-related renal function decline; adjust based on CrCl. |
| 1st trimester | Levetiracetam crosses the placenta. Data from pregnancy registries do not indicate a significantly increased risk of major congenital malformations compared to untreated epilepsy, but an increased risk of neural tube defects has been suggested in some studies. The drug is often continued in pregnancy to control seizures, as seizure activity poses risks to both mother and fetus. |
| 2nd trimester | Continued use may be necessary. No specific trimester-specific risks have been identified beyond those in the first trimester. Monitoring of drug levels and adjustment of dose may be required due to pregnancy-induced pharmacokinetic changes. |
| 3rd trimester | Continued use carries a risk of neonatal sedation, withdrawal symptoms, or adverse effects if used near term. The drug may cause vitamin K deficiency, increasing bleeding risk in the neonate; prophylactic vitamin K administration is recommended. |
Clinical note
No significant drug interactions May cause behavioral abnormalities including psychosis and aggression.
| FDA category | Human |
| Placental transfer |
■ FDA Black Box Warning
No FDA black box warnings.
| Common Effects | Somnolence |
| Serious Effects |
Hypersensitivity to levetiracetam or any of its excipients
| Precautions | Psychiatric reactions: Behavioral abnormalities including agitation, hostility, anxiety, apathy, depersonalization, and psychosis, Somnolence and fatigue: May impair cognitive and motor skills, Serious dermatological reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis (rare), Hematologic abnormalities: Decreased red blood cell, white blood cell, and platelet counts, Suicidal behavior and ideation: Increased risk in patients taking antiepileptic drugs, Seizure exacerbation or increase in seizure frequency |
| Food/Dietary | No significant food interactions; can be taken with or without food. Grapefruit and grapefruit juice do not affect levetiracetam. |
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| Levetiracetam readily crosses the placenta; cord blood concentrations approximate maternal plasma levels, indicating extensive placental transfer. |
| Breastfeeding | Levetiracetam is excreted into breast milk in low to moderate amounts, with relative infant doses estimated at 5-6% of the maternal weight-adjusted dose. No adverse effects have been consistently reported in breastfed infants. The benefit of breastfeeding likely outweighs the minimal risk, particularly given the risk of untreated maternal epilepsy. Monitor the infant for drowsiness and adequate weight gain. |
| Lactation Rating | L2 |
| Teratogenic Risk | First trimester: Increased risk of major congenital malformations (e.g., neural tube defects, cardiac anomalies) with a relative risk of 1.5-2.0 compared to unexposed. Second/third trimester: Risk of neurodevelopmental deficits (e.g., lower IQ, autism spectrum disorders) and growth restriction. Neonatal: Potential for sedative withdrawal symptoms. |
| Fetal Monitoring | Maternal: Serum levetiracetam levels monthly, seizure frequency, adverse effects (dizziness, sedation). Fetal: Level II ultrasound at 18-20 weeks for structural anomalies; consider fetal echocardiogram. Neonatal: Observe for withdrawal signs (irritability, poor feeding) for 48 hours after birth. |
| Fertility Effects | No evidence of altered fertility in women or men. Not associated with significant hormonal changes or menstrual irregularities. |
| Clinical Pearls | Levetiracetam is a unique broad-spectrum AED with minimal drug-drug interactions, making it useful for patients on polypharmacy. Dose adjustment based on creatinine clearance is essential as it is primarily renally excreted. Monitor for behavioral side effects (e.g., aggression, psychosis), especially in children and elderly. IV formulation can be given over 15 minutes; oral and IV doses are bioequivalent. |
| Patient Advice | Take exactly as prescribed; do not stop abruptly due to risk of increased seizures. · Report any unusual mood changes, aggression, or suicidal thoughts to your doctor immediately. · May cause dizziness or drowsiness; avoid driving until you know how the medication affects you. · Store at room temperature away from moisture and heat. |