Levetiracetam

1. Drug Name

• Generic Name: Levetiracetam

• Brand Names: Keppra, Keppra XR, Spritam

2. Drug Classification

• Class: Anticonvulsant

• Subclass: Pyrrolidine derivative

3. Mechanism of Action

• Levetiracetam primarily acts by binding to the synaptic vesicle protein SV2A in the brain, which modulates neurotransmitter release, particularly glutamate and GABA. This action stabilizes neuronal activity by inhibiting hyper-synchronization of neuronal firing, helping to prevent seizure propagation.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Nearly 100% (well-absorbed orally with minimal effect of food on absorption).

  • Tmax: ~1 hour for immediate-release; extended with XR formulations.

• Distribution:

  • Volume of Distribution (Vd): Approximately 0.5–0.7 L/kg.

  • Protein Binding: Very low (<10%), reducing potential for drug interactions.

• Metabolism:

  • Primarily hydrolyzed to inactive metabolites by plasma esterases rather than hepatic enzymes, which minimizes liver-based interactions.

• Excretion:

  • Half-life (t½): 6–8 hours in adults; extended in renal impairment.

  • Routes: Primarily excreted unchanged in urine (over 66%).

• Special Considerations:

  • Renal Impairment: Requires dose adjustment due to reduced clearance.

5. Indications

• Primary Indications:

  • Epilepsy: Approved for use in adults and children for partial-onset seizures, myoclonic seizures in juvenile myoclonic epilepsy, and generalized tonic-clonic seizures in idiopathic generalized epilepsy.

• Off-label Uses:

  • Used in some cases for status epilepticus as adjunctive therapy when other antiepileptics are ineffective.

• Special Populations:

  • Effective and approved for pediatric patients with specific seizure types; also used in adults for long-term seizure management.

6. Dosage and Administration

• Adult Dosing:

  • Partial-Onset Seizures: Start with 500 mg twice daily, increasing as needed up to 1,500 mg twice daily.

  • Extended-Release (XR) Formulations: Start with 1,000 mg once daily, titrated up to a maximum of 3,000 mg daily.

• Pediatric Dosing:

  • Dose varies by age and weight; generally, 10 mg/kg twice daily, titrating up to 30 mg/kg/day for children over 4 years.

• Dose Adjustments:

  • Renal Impairment: Adjust dose based on creatinine clearance (CrCl) levels.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to levetiracetam or its components.

• Relative Contraindications:

  • Renal Disease: Dose adjustments needed for significant renal impairment.

  • Behavioral Disorders: Caution due to risk of mood and behavioral changes.

8. Warnings and Precautions

• Suicidality: Increased risk of suicidal ideation and behavior, similar to other antiepileptic drugs; monitor patients closely for mood changes.

• Behavioral Changes: Aggression, irritability, mood swings, and psychosis have been reported, particularly in patients with a history of psychiatric disorders.

• Hematologic Abnormalities: Rare cases of pancytopenia and leukopenia; periodic blood counts may be advisable.

• Pregnancy and Lactation: Category C; should be used in pregnancy only if benefits outweigh risks. It is excreted in breast milk, so monitor for potential adverse effects in nursing infants.

9. Adverse Effects

• Common Adverse Effects:

  • CNS Effects: Drowsiness, dizziness, headache, fatigue.

  • Psychiatric Symptoms: Irritability, aggression, mood swings, and somnolence.

• Less Common but Clinically Significant:

  • GI Effects: Nausea, vomiting, diarrhea.

• Rare/Serious:

  • Hematologic Effects: Pancytopenia, leukopenia, thrombocytopenia.

  • Hypersensitivity Reactions: Rare reports of severe skin reactions (Stevens-Johnson syndrome).

  • Neuropsychiatric Effects: Suicidal ideation, psychosis, hallucinations.

10. Drug Interactions

• Minimal Metabolic Interactions: Due to low hepatic metabolism, levetiracetam has a low risk of interactions with CYP-modulating drugs.

• Alcohol and CNS Depressants: Concurrent use may increase the risk of CNS depression.

• Oral Contraceptives: No significant interaction; does not impact hormonal contraceptive efficacy.

11. Clinical Pharmacology

• Pharmacodynamics: Modulates neuronal firing via SV2A interaction, reducing seizure activity without affecting glutamate or GABA directly. The exact therapeutic mechanism remains partially understood but is unique compared to other anticonvulsants.

12. Special Populations

• Pregnancy: Category C; while human data are limited, animal studies suggest potential adverse fetal effects.

• Lactation: Excreted in breast milk; monitor breastfed infants for sedation and irritability.

• Geriatrics: May require dose adjustment based on renal function.

• Pediatrics: Approved for specific seizure indications in children as young as 1 month (dose adjustments based on weight and age).

13. Therapeutic Uses

• First-Line: For partial-onset seizures, myoclonic seizures in juvenile myoclonic epilepsy, and generalized tonic-clonic seizures in adults and children.

• Adjunctive Therapy: Often used as add-on therapy in refractory cases of epilepsy when other antiepileptics are insufficient.

• Off-Label: Has shown efficacy in some cases of status epilepticus when used as an adjunct.

14. Monitoring and Follow-Up

• Behavioral and Mood Assessments: Regular evaluations for changes in mood, behavior, or suicidality, especially during dose initiation or adjustments.

• Renal Function Tests: Especially in patients with pre-existing renal conditions; monitor for dose adjustments.

• Hematologic Monitoring: Periodic CBCs may be warranted in long-term use or if patient exhibits signs of infection or bleeding.

15. Overdose Management

• Symptoms of Overdose: Drowsiness, aggression, agitation, respiratory depression, and potentially coma.

• Treatment:

  • Supportive Measures: Ensure airway management and symptomatic care.

  • Hemodialysis: Effective due to low protein binding and renal excretion of levetiracetam, especially in cases of severe overdose.

16. Patient Counseling Information

• Key Points:

  • Take medication at the same time every day and do not discontinue abruptly due to seizure risk.

  • Mood Changes: Report any new or worsening mood changes, including irritability, aggression, or suicidal thoughts.

• Signs to Watch For:

  • Skin rash, persistent dizziness, or drowsiness; consult a physician if these occur.

• Lifestyle Considerations:

  • Avoid alcohol and other CNS depressants due to potential additive sedative effects.

  • Discuss any upcoming pregnancy plans with a healthcare provider.