Levetiracetam

Generic Name: Levetiracetam
Drug Class: Anticonvulsant / Antiepileptic
ATC Code: N03AX14

Common Brand Names: Keppra, Keppra XR, Elepsia XR, Spritam (3D-printed formulation), Levetiracetam Accord, Levetiracetam Teva

Regulatory Category: Prescription-only medicine
Formulations: Oral tablets, oral solution, extended-release tablets, and intravenous infusion

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Chemical and Pharmacological Profile

• Chemical Formula: C8H14N2O2

• Molecular Weight: 170.21 g/mol

• Structure: A pyrrolidone derivative unrelated to other antiepileptic drug classes

• Stereochemistry: Levetiracetam is the S-enantiomer of etiracetam

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Mechanism of Action

Levetiracetam acts by a unique, non-classical antiepileptic mechanism. Although its full mechanism is not completely understood, its primary target is the synaptic vesicle protein 2A (SV2A):

• SV2A binding: Modulates neurotransmitter release, especially glutamate, reducing neuronal excitability

• Calcium modulation: Partially inhibits N-type calcium channels

• No effect on GABAergic transmission directly

• No significant effect on sodium channels, unlike classical AEDs such as phenytoin or carbamazepine

This novel mechanism contributes to broad-spectrum anticonvulsant activity and a favorable interaction profile with other drugs.

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Indications

Levetiracetam is approved for use in adults and children for:

1. Partial-onset seizures with or without secondary generalization (adjunctive or monotherapy)

2. Myoclonic seizures in juvenile myoclonic epilepsy (adjunctive therapy)

3. Primary generalized tonic-clonic seizures (adjunctive therapy in generalized epilepsy)

4. Status epilepticus (off-label, IV form)

5. Perioperative seizure prophylaxis (investigational/off-label use)

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Dosage and Administration

Adults (Oral):

• Initial dose (adjunctive or monotherapy): 500 mg twice daily

• Titration: Increase by 500 mg every 2 weeks based on response

• Usual maintenance dose: 1000 to 3000 mg/day in 2 divided doses

Extended-Release Form:

• Once-daily dosing

• Available in 500 mg, 750 mg, and 1000 mg strengths

Children (≥1 month):

• Dose based on body weight (mg/kg)

• Starting dose: 10 mg/kg twice daily

• Maintenance: Up to 30–60 mg/kg/day in divided doses

IV Formulation:

• Same dosing as oral; infused over 15 minutes

• Used when oral therapy is not feasible

Administration Notes:

• May be taken with or without food

• Oral solution may be used in pediatric or dysphagic patients

• Switching between oral and IV forms does not require dose adjustment

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Pharmacokinetics

• Absorption: Rapid and nearly complete oral bioavailability (~100%)

• Peak plasma concentration: 1 hour (IR); 4 hours (XR)

• Distribution: Low plasma protein binding (<10%)

• Metabolism: Minimal hepatic metabolism (not CYP450-mediated)

• Elimination: Renal (66% excreted unchanged); adjust in renal impairment

• Half-life: ~6–8 hours (longer in elderly or renal impairment)

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Contraindications

• Known hypersensitivity to levetiracetam or any inactive ingredient

• Caution in patients with suicidal ideation, depression, or psychiatric disorders

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Warnings and Precautions

1. Neuropsychiatric Effects:

   • Irritability, aggression, mood changes, depression

   • Suicidal ideation and behavior: monitor closely, especially during dose titration

2. Behavioral Symptoms in Children:

   • Up to 17% may experience abnormal behavior or agitation

   • Psychosis reported, though rare

3. Hematologic Abnormalities:

   • Rare cases of thrombocytopenia, leukopenia, pancytopenia

4. Withdrawal Risk:

   • Abrupt discontinuation can provoke status epilepticus

   • Taper over at least 1–2 weeks when stopping

5. Renal Impairment:

   • Dose adjustment required due to renal clearance

   • Monitor renal function (eGFR)

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Adverse Effects

Common (≥1%):

• Drowsiness, fatigue

• Dizziness

• Irritability, aggression (especially in children)

• Headache

• Nasopharyngitis

• Anorexia

• Asthenia

Less Common:

• Anxiety, depression, insomnia

• Coordination difficulties (ataxia)

• Memory impairment

• Diplopia, vertigo

• Abnormal liver function tests

• Rash, pruritus

Rare/Severe:

• Psychosis, suicidal thoughts

• Stevens-Johnson syndrome

• Pancytopenia or thrombocytopenia

• Drug reaction with eosinophilia and systemic symptoms (DRESS)

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Drug Interactions

Levetiracetam has a low interaction potential, making it favorable for polytherapy:

• Does NOT inhibit or induce CYP450 enzymes

• No significant interaction with oral contraceptives, warfarin, digoxin, or most other AEDs

Minimal interactions with:

• Carbamazepine

• Lamotrigine

• Valproic acid

• Phenytoin

However, co-administration with CNS depressants (e.g., alcohol, sedatives) may enhance sedation and psychomotor impairment.

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Use in Pregnancy and Lactation

Pregnancy:

• Classified as Pregnancy Category C (US FDA)

• Human pregnancy registries suggest low risk of congenital malformations compared to older AEDs

• May be preferred in women planning pregnancy, but risks vs. benefits must be weighed

Lactation:

• Levetiracetam is excreted in breast milk

• Limited data suggests low infant serum levels and minimal adverse effects

• Breastfeeding is generally considered acceptable under medical supervision

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Overdose and Toxicity

Symptoms:

• Somnolence, agitation, respiratory depression

• Aggression, reduced consciousness

• Seizures (rarely paradoxically triggered at very high doses)

Management:

• Supportive care

• Activated charcoal (if recent ingestion)

• Hemodialysis may enhance clearance in severe overdose

• No specific antidote available

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Comparison with Other Antiepileptics

Drug	Mechanism	Key Features
Levetiracetam	SV2A modulator	Broad-spectrum, low interaction risk
Lamotrigine	Na⁺ channel blocker, glutamate inhibition	Mood stabilizing, skin rash risk
Carbamazepine	Na⁺ channel blocker	Autoinducer, many interactions
Valproic acid	GABA potentiation	Highly teratogenic, broad-spectrum
Phenytoin	Na⁺ channel blocker	Narrow therapeutic index, cosmetic side effects

Levetiracetam is often preferred for ease of use, minimal monitoring, and broad-spectrum coverage, especially in polytherapy regimens.

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Patient Counseling Points

• Take exactly as prescribed, same time daily, with or without food

• Do not stop abruptly – taper slowly under supervision

• May cause drowsiness or dizziness – caution with driving or machinery

• Report mood changes, irritability, depression, or suicidal thoughts promptly

• Inform physician if pregnant, planning pregnancy, or breastfeeding

• Avoid alcohol and other CNS depressants to reduce additive sedative effects

• Use oral solution carefully measured with a dosing syringe

• Store oral solution and tablets at room temperature, away from moisture