Levetiracetam is a novel, antiepileptic drug used in the treatment of partial seizures, myoclonic seizures, and tonic-clonic seizures. In 2000, the FDA approved the use of the oral formulation as adjunctive therapy for treatment of focal seizures, myoclonic seizure, and primary generalized seizures. The FDA approved intravenous levetiracetam (LEV) in 2006 for use in patients older than 15 years, as adjunctive anticonvulsant therapy when the oral formulation is not tolerated. In Europe, it is approved for treatment of partial seizures as a single agent and as an add-on treatment for partial seizures, tonic-clonic seizures, and myoclonic seizures.
It is chemically unrelated to other antiepileptic drugs. Its favorable safety profile, distinct mechanism of action, and fewer drug interactions make it an attractive therapeutic choice for treatment of seizures.
The mechanisms by which LEV exerts its antiepileptic effects are not clearly defined. The most relevant mechanism of action is believed to be through binding to a unique protein known as synaptic vesicle protein 2A (SV2A). SV2A protein is a part of secretory vesicle membranes that mediates calcium-dependent vesicular neurotransmitter release. Binding of LEV to SV2A appears to decrease the rate of vesicle release.
Levetiracetam is rapidly absorbed and has very high (96%) bioavailability. Peak plasma concentration is achieved in about an hour after oral administration. Food may delay the time to maximum concentration by about half an hour, but it does not affect the extent of absorption. Only less than 10% is protein bound, so it does not compete with other drugs for protein binding sites. It is not extensively metabolized, and almost 66% is excreted unchanged by kidneys. The main metabolic pathway is enzymatic hydrolysis of acetamide group. Metabolites have no pharmacological activity and are renally excreted. Glomerular filtration with partial tubular reabsorption is the mechanism of excretion and is correlated with creatinine clearance. Cytochrome P450 system does not affect its metabolism. Plasma half-life is about 6 to 8 hours in adults but can be increased by 2 to 3 hours in elderly as the creatinine clearance decreases with age. Dose adjustment is needed in renal impairment. Because it is not metabolized by the liver and has no significant protein binding, pharmacokinetic interactions are fewer. LEV has linear pharmacokinetics over a dose range of 500 to 5000 mg, which means that serum concentration is proportional to the dose. Steady state is achieved after 2 days of twice-daily dosing. Effective serum level is not known. Toxic and therapeutic concentrations are not defined, but measuring serum levels can help assess compliance.
Bioavailability and metabolism of the extended-release form are similar to immediate release formulation. However, time to reach peak plasma concentration is 3 hours longer with extended release formulation.
The intravenous formulation is used when patients are unable to take oral medications. Peak plasma concentration is reached in 5 to 15 minutes with intravenous use. Otherwise, the pharmacokinetic profile is same as an oral formulation.
LEV is available in oral and intravenous (IV) formulations. Oral forms are available in immediate-release and extended-release forms.
Minimum recommended dose is 500 mg twice daily. Some older adults may respond to dose as low as 500 mg per day. It should be started at a low dose and titrated up for clinical response. Increase the dose at 250 or 500 mg at 1 to 2-week intervals until the clinical response is achieved. The maximum recommended dose is 3000 mg per day. Rapid dose escalation can lead to adverse effects. An immediate-release form is dosed twice daily and extended-release forms once daily. Therapeutic serum concentration is not established for LEV and dosage is guided by clinical response.
Efficacy of more than 3000 mg/day dose is not fully established. Some suggest that dose can be increased up to 4000 mg /day in patients who have shown clear response but have occasional breakthrough seizures. There are some reports of seizure exacerbation with higher doses, and the physician should keep that in mind while using higher doses.
The total daily dosage of IV LEV is equivalent to oral. It is administered as a 15-minute infusion. There is no evidence to use a loading dose.
It is also used off-label sometimes for status epilepticus. The dose used is 1000 to 3000 mg IV infusion at a rate of 2 mg/kg per minute or a single dose of 60 mg/kg.
LEV may be used safely (with caution) in children older than 4 years of age. The recommended starting dose is 20 mg/kg per day in 2 divided doses. It can be titrated up by 20 mg/kg every 2 weeks up to maximum dose of 60 mg/kg per day.
Dosage adjustment is generally not needed for hepatic impairment. However, there are reports that total body clearance of LEV is reduced by half in severe liver disease, Child-Pugh C. Therefore, in patients with severe liver cirrhosis, half of the recommended dose should be initiated.
LEV is excreted through kidneys, so renal impairment decreases the rate of elimination, necessitating dose reduction.
LEV is a pregnancy category C drug. Maternal serum levels can fall significantly during the third trimester, and monitoring of serum concentration should be used to guide dosing. No significant congenital abnormalities have been reported following maternal use of LEV. It is excreted in breast milk, but serum drug levels in infants have been shown to be low.
No significant drug interactions of LEV are observed with other anti-epileptics like phenytoin, valproic acid, carbamazepine, phenobarbital, primidone. No significant interactions with drugs like digoxin or warfarin.
LEV metabolism rate and its clearance may be increased in patients taking enzyme-inducing anti-epileptics like phenytoin, carbamazepine, and phenobarbital.
Since LEV can cause somnolence and CNS depression, it may enhance the CNS-depressant effect of alcohol, cannabis, and other drugs like azelastine, carbamazepine, opioids, among others.
Hypersensitivity reaction to LEV or any component of the formulation.
Baseline creatinine should be checked before initiating LEV therapy. Signs and symptoms of depression, suicidality, and psychosis should be closely monitored. Blood pressure should be monitored closely in children less than 4 years old.
Generally, no blood monitoring is required during therapy. Serum concentrations may help assess compliance and may be used as dosing guide in pregnant and elderly patients.
There are few known case of overdose with LEV in clinical trials. Drowsiness, somnolence, agitation, respiratory depression, and coma have been observed with LEV overdose. There is no antidote for LEV. General supportive measures, airway protection, monitoring vital signs are done on overdose patients. Poison control should be contacted. Hemodialysis may be needed in patients with significant renal impairment. Four-hour hemodialysis session can remove almost 50% of the drug.
|[Management of epilepsia in older]., Alberti A,Thomas B,Marchal C,, Presse medicale (Paris, France : 1983), 2018 Mar 23 [PubMed PMID: 29580905]|
|Comparative efficacy of unique antiepileptic drug regimens in focal epilepsy: An exploratory study., Legge AW,Detyniecki K,Javed A,Hirsch LJ,Kato K,Buchsbaum R,Chen B,Choi H,, Epilepsy research, 2018 Mar 10 [PubMed PMID: 29571152]|
|A meta-analysis of randomized controlled trials on levetiracetam in the treatment of pediatric patients with epilepsy., Zhang L,Wang C,Li W,, Neuropsychiatric disease and treatment, 2018 [PubMed PMID: 29559784]|
|Levetiracetam monotherapy for the treatment of infants with epilepsy., Arican P,Gencpinar P,Cavusoglu D,Olgac Dundar N,, Seizure, 2018 Feb 12 [PubMed PMID: 29453114]|
|Seizures and Choice of Antiepileptic Drugs Following Subarachnoid Hemorrhage: A Review., Mahmoud SH,Buxton J,, The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 2017 Nov [PubMed PMID: 29391074]|