Levetiracetam

Levetiracetam is a broad-spectrum antiepileptic drug (AED) widely used for treating multiple seizure types, including partial-onset, myoclonic, and generalized tonic-clonic seizures. 

Known for its favorable pharmacokinetics, minimal drug interactions, and availability in oral and IV forms, levetiracetam has become a cornerstone in both acute and long-term seizure management.

Levetiracetam: A Broad-Spectrum Antiepileptic Medication

Levetiracetam (brand name: Keppra) is a second-generation antiepileptic drug (AED) used to treat various types of seizures. It is available in multiple formulations, including immediate-release and extended-release tablets, oral solution, and intravenous (IV) infusion.

How Levetiracetam Works (Mechanism of Action)

Levetiracetam primarily works by binding to synaptic vesicle protein 2A (SV2A), a protein involved in the release of neurotransmitters. This binding reduces abnormal neuronal excitability and helps prevent seizures. 

Additional effects may include calcium channel inhibition and GABA and glutamate signaling modulation.

Uses and Applications of Levetiracetam

Clinical Applications of Levetiracetam: Levetiracetam is FDA-approved to treat various types of seizures.

Partial-Onset Seizures

Approved for monotherapy or adjunctive therapy for adults and children ≥1 month old.

Myoclonic Seizures

Approved as adjunctive therapy for adolescents ≥12 years with juvenile myoclonic epilepsy.

Primary Generalized Tonic-Clonic Seizures

Approved for adjunctive use in adults and children ≥6 years with idiopathic generalized epilepsy.

Off-Label Uses

Off-label uses include: 

• Status epilepticus
• Seizure prophylaxis in subarachnoid hemorrhage, TBI, neurosurgery
• Seizure control in palliative care

Benefits of Levetiracetam Treatment

Therapeutic advantages of levetiracetam in seizure management include:

Broad-Spectrum Efficacy

Levetiracetam is effective against multiple seizure types.

Favorable Pharmacokinetics

Levetiracetam features nearly 100% oral bioavailability, minimal hepatic metabolism, and low protein binding, reducing drug-drug interaction risks.

Flexible Formulations

It is available as oral tablets (IR/ER), oral solution, and IV for acute management.

Risks, Side Effects, and Potential Concerns with Levetiracetam

The following must be considered regarding Levetiracetam use:

Common Side Effects

Common side effects include somnolence, fatigue, dizziness, headache, irritability, and mood changes.

Psychiatric Reactions

Psychiatric reactions may include behavioral issues such as agitation, anxiety, depression, and suicidal ideation, especially in children or patients with a psychiatric history.

Rare but Serious Reactions

Rare but serious reactions may include:

• Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Anaphylaxis, pancytopenia, hepatotoxicity

FDA Warning (2023)

DRESS is a life-threatening hypersensitivity reaction—discontinue if suspected.

Dosage and Administration of Levetiracetam

Levetiracetam dosing and administration guidelines include:

Adults

• Start: 500 mg BID
• Titrate: Increase by 250–500 mg every 1–2 weeks
• Max: 3000 mg/day (up to 4000 mg in some cases)

Status Epilepticus (Off-label)

• 1000–3000 mg IV bolus or 60 mg/kg (up to 3 g)
• Rapid undiluted IV push may be safe and effective

Pediatrics

• Start: 20 mg/kg/day in 2 doses
• Max: 60 mg/kg/day

Renal Impairment

• Requires dose reduction based on creatinine clearance
• ESRD: 500–1000 mg/day + 250–500 mg post-dialysis

Hepatic Impairment

• No dose adjustment unless severe (Child-Pugh C)—start at 50% dose

Essential Monitoring and Precautions During Levetiracetam Treatment

• Baseline: Renal function (serum creatinine, eGFR)
• Mental Health: Monitor for behavioral changes, mood swings, suicidality
• Pediatrics: Monitor blood pressure in children <4 years
• Pregnancy: Monitor serum levels closely, especially in third trimester due to increased clearance
• Breastfeeding: Excreted in breast milk—monitor infants for sedation and growth

Interactions with Other Medications

• Low Interaction Potential: Not metabolized by CYP450 enzymes
• Enzyme Inducers (e.g., phenytoin, carbamazepine): May increase levetiracetam clearance
• Enzyme Inhibitors (e.g., valproate): May reduce clearance
• Additive CNS Depression: Alcohol, opioids, sedatives can increase side effects

Conclusion: Clinical Pearls

Levetiracetam has a low potential for drug interactions, making it an ideal choice for patients who are on multiple medications or have liver impairment, as the liver does not significantly metabolize it. 

However, behavioral side effects such as irritability, agitation, and mood changes are relatively common, especially in pediatric or psychiatric populations. These effects are often reversible with dose adjustments or discontinuation. 

The medication is highly versatile, with oral and intravenous formulations that make it suitable for use in emergency and outpatient settings. 

Levetiracetam plays a significant role in epilepsy care globally. It is included on the World Health Organization's Essential Medicines List and supports expanded treatment access in low—and middle-income countries. 

Additionally, levetiracetam is considered safer than many other antiepileptic drugs during pregnancy, with no established teratogenic risk beyond the population baseline. Nonetheless, therapeutic drug monitoring is advised during pregnancy, especially in the third trimester, due to increased drug clearance.