Levetiracetam

Usage

Levetiracetam is an anticonvulsant medication prescribed for the adjunctive treatment of partial-onset seizures in adults and children with epilepsy. It is also used for myoclonic seizures in patients 12 years and older with juvenile myoclonic epilepsy, and primary generalized tonic-clonic seizures in patients 12 years and older with idiopathic generalized epilepsy. Occasionally, levetiracetam has also been used in neonatal seizures and off label for treatment of certain psychiatric conditions.

Alternate Names

Levetiracetam is also known internationally by the same name. Some of the most common brand names are Keppra, Keppra XR, Spritam, and Elepsia XR.

How It Works

Pharmacodynamics: Levetiracetam’s precise mechanism of action is not fully understood, but it is thought to bind to the synaptic vesicle protein 2A (SV2A) in the brain. This binding may modulate neurotransmitter release and reduce neuronal excitability, thereby suppressing seizure activity.

Pharmacokinetics:

• Absorption: Levetiracetam is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations occurring within 1-1.5 hours. Food does not affect the extent of absorption. Bioavailability of IV and oral routes are nearly identical.
• Distribution: It is widely distributed throughout the body, including the brain and cerebrospinal fluid. It is minimally protein-bound.
• Metabolism: Levetiracetam undergoes minimal metabolism in the liver. The primary metabolite is inactive.
• Elimination: Primarily eliminated through renal excretion (approximately 66% unchanged), with a half-life of 6-8 hours. Because of this route of elimination, dosage adjustments are needed for patients with renal impairment.

Dosage

Standard Dosage

Adults:

• Initial: 500 mg twice daily (bid).
• Maintenance: 1000-3000 mg/day, divided bid.
• Extended Release: 1000 mg once a day, adjusted as needed; not to exceed 3000 mg per day.

Children (4-11 years and 12-17 years weighing <50 kg):

• Initial: 10 mg/kg bid.

• Maintenance: Titrate up to a maximum of 60 mg/kg/day, divided bid. Weight-based dosing is required until the patient reaches 50 kg. Dosages for this range vary from 250 mg to 1500 mg bid. At 50 kg, transition to the adult dosing strategy is recommended.

• Children (1-6 months to 3 years old): Dosing in this group is highly patient specific. Start at 10 mg/kg bid. If the patient is above 20 kg, either oral solution or tablets may be used, remembering that only whole tablets should be given. Patients below 20 kg should only receive the medication as an oral solution. Dosage may be titrated up to a maximum dose dependent on weight.

• Neonates (<1 month) Dosing in this age range is complicated, and is done intravenously, and a pediatric neurologist should be consulted prior to prescribing levetiracetam. Start with a loading dose of 40 mg/kg, followed by a maintenance dose, which is adjusted depending on the postnatal age of the neonate.

Special Cases:

• Elderly Patients: Dose adjustment may be needed based on renal function.
• Patients with Renal Impairment: Dose reduction is necessary based on creatinine clearance (CrCl). Guidelines are available outlining recommendations for levetiracetam dosing stratified based on severity of renal failure (CrCl >80 mL/min, 50-80 mL/min, 30-50 mL/min, <30 mL/min), with further guidance provided for patients on dialysis.
• Patients with Hepatic Dysfunction: Dose adjustment is generally not necessary for mild to moderate impairment. In severe hepatic impairment (Child-Pugh C), consider starting with half the recommended dose.
• Patients with Comorbid Conditions: Consider drug interactions and adjust as needed.

Clinical Use Cases

Levetiracetam is primarily used for seizure management. There are no specific dosage adjustments for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations other than those based on renal or hepatic function. In cases of status epilepticus, intravenous levetiracetam can be administered.

Side Effects

Common Side Effects:

• Somnolence/fatigue
• Dizziness
• Headache
• Asthenia/Weakness
• Coordination difficulties
• Infection
• Rash
• Nasopharyngitis
• Irritability
• Anorexia
• Anxiety

Rare but Serious Side Effects:

• Severe skin reactions: Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Suicidal ideation
• Psychosis/Hallucinations
• Anaphylaxis/Angioedema
• Pancreatitis
• Hepatic failure
• Renal impairment
• Neutropenia
• Leukopenia
• Thrombocytopenia
• Pancytopenia

Long-Term Effects:

Chronic complications from prolonged levetiracetam use are rare. However, patients should be monitored for any emerging neuropsychiatric or hematological issues.

Contraindications

• Hypersensitivity to levetiracetam

Drug Interactions

Levetiracetam has few clinically significant drug interactions. Enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine) may increase levetiracetam clearance. Conversely, enzyme inhibitors like valproate may decrease clearance. Concurrent use with CNS depressants (e.g., alcohol, benzodiazepines, opioids) can potentiate sedation.

Pregnancy and Breastfeeding

Levetiracetam is generally considered safe to use during pregnancy, but the lowest effective dose should be used. It is excreted in breast milk, and while generally considered safe, infants should be monitored for drowsiness and adequate weight gain.

Drug Profile Summary

• Mechanism of Action: Binds to SV2A, modulating neurotransmitter release and reducing neuronal excitability.
• Side Effects: Common: Somnolence, dizziness, headache, asthenia, coordination difficulties. Serious: SJS/TEN, suicidal ideation, psychosis.
• Contraindications: Hypersensitivity.
• Drug Interactions: Enzyme-inducing/inhibiting drugs, CNS depressants.
• Pregnancy & Breastfeeding: Generally safe, monitor infant for drowsiness and weight gain.
• Dosage: Adults: 1000-3000 mg/day divided bid. Children: weight-based dosing up to 60 mg/kg/day divided bid.
• Monitoring Parameters: Renal function (especially in elderly), liver function tests, complete blood counts, and mental status.

Popular Combinations

Levetiracetam is frequently used in combination with other antiepileptic drugs when monotherapy is inadequate for seizure control.

Precautions

• General Precautions: Monitor for neuropsychiatric and hematological side effects.
• Specific Populations:
  • Pregnant Women: Use lowest effective dose, monitor fetal development.
  • Breastfeeding Mothers: Monitor infant for drowsiness and weight gain.
  • Children & Elderly: Weight-based dosing for children, renal function monitoring for elderly.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Levetiracetam?

A: Adults: 1000-3000 mg/day divided bid. Children: weight-based dosing up to 60 mg/kg/day divided bid. Adjustments are necessary for patients with renal impairment or severe hepatic dysfunction. Neonates: loading dose of 40 mg/kg given intravenously, followed by maintenance dose, which needs adjustment depending on postnatal age.

Q2: How should Levetiracetam be administered?

A: Orally, with or without food. Intravenous administration is also possible, particularly for status epilepticus or patients unable to take oral medications.

Q3: What are the common side effects of Levetiracetam?

A: Somnolence, dizziness, headache, asthenia (weakness or lack of energy), and coordination difficulties are among the most common side effects.

Q4: Are there any serious side effects I should be aware of?

A: Yes, though rare, serious side effects include suicidal ideation, psychosis, severe skin reactions (SJS, TEN, DRESS), pancreatitis, hepatic failure, blood dyscrasias (neutropenia, thrombocytopenia, leukopenia, pancytopenia), and anaphylaxis/angioedema.

Q5: Can Levetiracetam be used during pregnancy?

A: It can be used if clinically necessary, but at the lowest effective dose. Careful monitoring of the pregnancy is required.

Q6: Is it safe to breastfeed while taking Levetiracetam?

A: Levetiracetam does pass into breast milk, but is generally considered safe. Closely monitor the infant for excessive drowsiness and ensure adequate weight gain.

Q7: Does Levetiracetam interact with other medications?

A: It has relatively few clinically significant drug interactions. The most important interactions are with enzyme-inducing and -inhibiting medications, which may affect levetiracetam clearance. Concurrent use with CNS depressants can enhance sedation.

Q8: How does renal impairment affect Levetiracetam dosing?

A: Renal impairment reduces levetiracetam clearance, necessitating dosage adjustments. Specific recommendations are based on CrCl, with additional considerations for patients on dialysis.

Q9: How is Levetiracetam metabolized?

A: It undergoes minimal metabolism. Primarily excreted unchanged by the kidneys (about 66%).

Q10: What is the role of therapeutic drug monitoring (TDM) for Levetiracetam?

A: Routine TDM is not generally recommended. Dosage is usually guided by clinical response and tolerability. However, TDM may be useful in specific situations, such as pregnancy, suspected toxicity, or difficulty achieving seizure control.