Levetiracetam


Article Author:
Anil Kumar


Article Editor:
Renu Kadian


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Phillip Hynes


Updated:
4/3/2019 10:48:14 AM

Indications

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.

Uses

  • Myoclonic seizures: It is approved for use as adjunctive therapy in the treatment of myoclonic seizures in adults and juvenile myoclonic epilepsy in adolescents 12 years and older.
  • Partial seizures: It can be used as adjunctive therapy for treating partial seizures in adults and children one month or older with epilepsy.
  • Primary generalized tonic-clonic seizure: Used for adjunctive therapy for treatment of primary generalized tonic conic seizure in adults and children more than 5 years old with idiopathic generalized epilepsy.
  • It is sometimes used off-label (non-FDA-approved) for status epilepticus and seizure prophylaxis in subarachnoid hemorrhage.[1][2][3]

Mechanism of Action

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.

Pharmacodynamics/Kinetics

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.[4][5][6]

Administration

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.

Hepatic impairment

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.

Renal Impairment

LEV is excreted through kidneys, so renal impairment decreases the rate of elimination, necessitating dose reduction.

Pregnancy

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. [4][5][6]

Adverse Effects

  • Central nervous system (CNS): Most common side effects are neurobehavioral like somnolence, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, the decline in cognition and increased suicide risk. Most of the time side effects are mild. About 1% patients experience serious side effects like psychosis, hallucinations and suicidal thoughts. These side effects are more common in the first month of treatment but can develop any time during treatment and improve once the drug is discontinued. Dose reduction is associated with improvement in behavioral problems.
  • Cardiovascular (CVS): Increased diastolic blood pressure in infants and children
  • Gastrointestinal (GI): Vomiting, abdominal pain, nausea, anorexia
  • Infections: Pharyngitis, rhinitis has been reported in 7% to 15% patients.
  • Hypersensitivity reactions: Rarely, serious, life-threatening reactions have been reported with use of LEV. These include angioedema, anaphylaxis, Steven Johnson syndrome, toxic epidermal necrolysis, hives, respiratory distress.
  • Hematologic: Leukopenia, eosinophilia, and rarely pancytopenia have been reported with use of LEV.

Drug Interactions

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.[4][5][6][7][8]

Contraindications

Hypersensitivity reaction to LEV or any component of the formulation.

Monitoring

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.[9]

Toxicity

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.[10]

Enhancing Healthcare Team Outcomes

An interprofessional team involving the clinician, nurse, and pharmacist assisting and educating the patient with the administration and regular dosing of the drug will result in the best patient outcome. [Level V]


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Levetiracetam - Questions

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Which of the following is an anticonvulsant?



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Which of the following medications is not eliminated unchanged in the urine?



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Select the medication that is not metabolized by the liver.



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Which of the following antiseizure medications does not inhibit voltage dependent sodium channels?



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Levetiracetam is eliminated by:



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An 8-year-old male is brought in by his mother for a follow-up visit after a recent diagnosis of tonic-clonic seizures. The patient has been taking levetiracetam daily for his seizure disorder. He has no other medical conditions and takes no other medications. His mother reports no seizure activity in the last 6 months. She also states that he is a happy, friendly child, but as of late, he has become aggressive towards his siblings. She states that he has not had behavioral issues before. Gross motor, fine motor, and language development are all normal. The neurological exam reveals no focal deficits. What is the most likely cause of this patient's change in behavior?



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Which of the following medication does not have any significant interaction with other antiepileptic drugs?



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Which of the following is false about levetiracetam?



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A 70-year-old male is brought to the clinic by his family for changes in behavior including increased agitation and aggression over the past 2 weeks. He has a history of hypertension, primary generalized tonic-clonic seizures, and mild cognitive impairment. His medications include divalproex sodium, amlodipine, and levetiracetam that was started 6 weeks ago for uncontrolled seizures. On examination, his vital signs are normal and the neurologic exam is nonfocal. He appears restless. What most likely explains his symptoms?



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Which of the following is true about levetiracetam?



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A 54-year-old female with a history of partial seizures presents with uncontrolled seizures. Her current medications include carbamazepine. Which of the following would be a relative contraindication for starting levetiracetam?



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Levetiracetam - References

References

[Management of epilepsia in older]., Alberti A,Thomas B,Marchal C,, Presse medicale (Paris, France : 1983), 2018 Mar 23     [PubMed]
Dewolfe JL,Szaflarski JP, Levetiracetam use in the critical care setting. Frontiers in neurology. 2013;     [PubMed]
Farooq MU,Bhatt A,Majid A,Gupta R,Khasnis A,Kassab MY, Levetiracetam for managing neurologic and psychiatric disorders. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2009 Mar 15;     [PubMed]
Noyer M,Gillard M,Matagne A,Hénichart JP,Wülfert E, The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. European journal of pharmacology. 1995 Nov 14;     [PubMed]
Patsalos PN, The pharmacokinetic characteristics of levetiracetam. Methods and findings in experimental and clinical pharmacology. 2003 Mar;     [PubMed]
Patsalos PN, Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacology     [PubMed]
Cereghino JJ,Biton V,Abou-Khalil B,Dreifuss F,Gauer LJ,Leppik I, Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000 Jul 25;     [PubMed]
Beran RG,Berkovic SF,Black AB,Danta G,Hiersemenzel R,Schapel GJ,Vajda FJ, Efficacy and safety of levetiracetam 1000-3000 mg/day in patients with refractory partial-onset seizures: a multicenter, open-label single-arm study. Epilepsy research. 2005 Jan;     [PubMed]
Jarvie D,Mahmoud SH, Therapeutic Drug Monitoring of Levetiracetam in Select Populations. Journal of pharmacy     [PubMed]
Choonara I, Anti-Epileptic Drug Toxicity in Children. Children (Basel, Switzerland). 2018 May 1;     [PubMed]

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