Levetiracetam

Levetiracetam is a broad-spectrum antiseizure medicine of the pyrrolidone class, used for focal, generalised tonic-clonic and myoclonic seizures and as a parenteral option in status epilepticus. Its strengths are rapid titration, few interactions and a wide safety margin. Its main limits are behavioural adverse effects and the need for renal dose adjustment.

Mechanism. Binds synaptic vesicle protein 2A and modulates neurotransmitter release. It also partly inhibits N-type calcium channels. It does not act directly on sodium channels or GABA receptors.

Pharmacokinetics. Oral bioavailability is near 100%, and food delays but does not reduce absorption. Protein binding is under 10%. About 66% is excreted unchanged in urine and about 24% is hydrolysed by blood enzymes, not by cytochrome P450. Half-life is 6 to 8 hours, longer in older adults and renal impairment. Kinetics are linear and steady state is reached in about 2 days.

First-line use. Focal seizures (monotherapy or adjunct), generalised tonic-clonic seizures, and myoclonic seizures in juvenile myoclonic epilepsy. Treatment is long term, and withdrawal is considered by a specialist only after at least 2 seizure-free years.

• Adults and adolescents over 50 kg, focal seizures, oral levetiracetam: start 250 mg twice daily for 2 weeks, then 500 mg twice daily. Increase by 250 mg twice daily every 2 weeks as needed. Usual maintenance 1000 to 3000 mg daily in two divided doses. Usual maximum 3000 mg daily. Doses up to 4000 mg daily are used by some specialists with limited evidence of added benefit.

• Adjunct therapy can start at 500 mg twice daily and rise by 500 mg twice daily every 2 weeks.

• Myoclonic seizures, age 12 years and over: 500 mg twice daily, increased by 500 mg twice daily every 2 weeks to a usual maximum of 1500 mg twice daily.

• Children 6 months to 17 years under 50 kg: 10 mg/kg twice daily, increased by 10 mg/kg twice daily every 2 weeks to a usual maximum of 30 mg/kg twice daily. Infants 1 month to under 6 months: 7 mg/kg twice daily, increased to a maximum of 21 mg/kg twice daily. Use the oral solution for weights under 25 kg.

• Oral and intravenous routes are interchangeable at the same total daily dose and frequency.

Emergency use. Status epilepticus after a benzodiazepine has failed:

• Levetiracetam intravenous loading dose 60 mg/kg (maximum 4500 mg) as a single dose over 10 to 15 minutes. Begin maintenance of 500 to 1500 mg every 12 hours about 12 hours later, adjusted to kidney function.

Kidney function. Adult maintenance dose by creatinine clearance:

Liver and weight. No change is needed in mild to moderate liver impairment. In severe liver impairment with creatinine clearance under 60 mL/min, halve the daily maintenance dose, because creatinine clearance underestimates renal impairment in this setting. Adults use fixed doses regardless of weight; children are dosed by weight.

Contraindications. Hypersensitivity to levetiracetam or other pyrrolidone derivatives.

Serious adverse effects. Psychosis, hallucinations, severe aggression and suicidal ideation. Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (rare). Pancytopenia, neutropenia, angioedema, rhabdomyolysis. Seizure relapse on abrupt withdrawal.

Common adverse effects. Somnolence, fatigue, dizziness, headache, irritability and mood change. Behavioural effects are more frequent in children and in people with prior psychiatric illness.

Interactions. Few. Enzyme-inducing antiseizure medicines such as carbamazepine, phenytoin and phenobarbital modestly lower levetiracetam levels. Levetiracetam does not meaningfully alter hormonal contraceptives or most antiretrovirals. Macrogol laxatives may reduce absorption, so avoid giving them within 1 hour before or after a dose.

Common prescribing errors. Not reducing the dose in renal impairment. Under-dosing in status epilepticus (for example a flat 1000 mg instead of 60 mg/kg). Abrupt withdrawal. Confusing the 100 mg/mL solution with the 500 mg/5 mL injection concentrate.

Special groups.

• Pregnancy: among the antiseizure medicines with the lowest malformation risk. Clearance rises and levels can fall by up to 50% late in pregnancy, so titrate to seizure control and return to the pre-pregnancy dose within weeks of delivery. Folic acid 5 mg daily is started before conception.

• Breastfeeding: infant exposure is moderate and use is usually acceptable. Watch for sedation and poor feeding.

• Older adults: lower clearance; dose by creatinine clearance and watch for confusion and falls.

• Regional: where supply is intermittent, stock-outs and abrupt interruption are a common cause of breakthrough seizures and status epilepticus, so plan continuity of supply.

Formulations. Tablets 250, 500, 750 and 1000 mg. Oral solution 100 mg/mL. Prolonged-release tablets 500 and 750 mg. Intravenous concentrate 500 mg in 5 mL. Tablets are taken with or without food.

Preparation. Dilute the intravenous concentrate in at least 100 mL of 0.9% sodium chloride, 5% glucose or Ringer lactate. Maintenance doses run over 15 minutes. Loading doses for status epilepticus run over 10 to 15 minutes.

Monitoring. Baseline creatinine clearance, then recheck when kidney function changes. Review mood, irritability and behaviour at each visit. Drug levels are not routinely needed, and a commonly quoted reference range is 12 to 46 mg/L.

Stopping. Reduce by 250 mg twice daily every 2 to 4 weeks in adults, and by 10 mg/kg twice daily every 2 weeks in children. Stop promptly for severe skin reactions or severe psychiatric effects.

Referral and escalation. Refer to neurology when seizures persist despite two well-chosen, tolerated medicines, when pregnancy is planned, or when psychiatric symptoms emerge. Seizures continuing after the second-line drug define refractory status epilepticus and need critical care.