Levetiracetam (levetiracetam)

Levetiracetam therapy should not be discontinued abruptly.

When switching from oral to IV levetiracetam therapy, the initial total daily dosage of IV levetiracetam should be equivalent to the daily dose and frequency of oral levetiracetam. At the completion of the IV treatment period, the patient may be switched back to oral levetiracetam at the equivalent daily dose and frequency that was administered IV.

Levetiracetam is administered orally (as immediate-release tablets, extended-release tablets, or oral solution). The drug also may be administered by IV infusion in patients in whom oral therapy is temporarily not feasible.

Commercially available levetiracetam conventional (immediate-release) tablets, extended-release tablets, oral solution, and IV formulations have been shown to be bioequivalent.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Levetiracetam/Apixaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Levetiracetam may decrease the efficacy of apixaban.

CLINICAL EFFECTS: Concurrent use of levetiracetam may result in decreased effectiveness of apixaban.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of levetiracetam in patients receiving apixaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on apixaban. If concurrent use is warranted, monitor patients closely for decreased response to apixaban.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of 2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26 (1.13-4.54) compared to controls.(5) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(6) In a case report, a 54 year old man with a complicated medical history including paroxysmal atrial fibrillation, heart failure, and epilepsy who was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg twice daily, taken simultaneously with levetiracetam. On day 10 of dabigatran, trough levels were normal but Cmax was subtherapeutic. Separation of dabigatran administration to 4 hours before levetiracetam resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL. Over 32 months of follow-up, no hemorrhagic or ischemic events occurred.(7) A retrospective study of 320 patients with atrial fibrillation on DOAC therapy for secondary stroke prevention compared the incidence of ischemic stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing medications (n=43), P-gp inducing medications (n=13), or no interacting medications (n=264). Twenty of the patients were on levetiracetam. There was no statistically significant difference between any of the groups.(8) A small prospective cohort study of 19 patients on the combination of levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4 patients on rivaroxaban) did not find a significant correlation between levetiracetam and DOAC concentrations. One patient who was on low-dose apixaban had low apixaban levels, and there were no thromboembolic events in the 1388 +/- 994 days of follow-up.(9)

Levetiracetam/Dabigatran

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Levetiracetam may decrease the efficacy of dabigatran.

CLINICAL EFFECTS: Concurrent use of levetiracetam may result in decreased effectiveness of dabigatran.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of levetiracetam in patients receiving dabigatran should be approached with caution. Consider alternative anticonvulsants in patients maintained on dabigatran. If concurrent use is warranted, monitor patients closely for decreased response to dabigatran.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of 2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26 (1.13-4.54) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5) In a case report, a 54 year old man with a complicated medical history including paroxysmal atrial fibrillation, heart failure, and epilepsy who was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg twice daily, taken simultaneously with levetiracetam. On day 10 of dabigatran, trough levels were normal but Cmax was subtherapeutic. Separation of dabigatran administration to 4 hours before levetiracetam resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL. Over 32 months of follow-up, no hemorrhagic or ischemic events occurred.(6) A retrospective study of 320 patients with atrial fibrillation on DOAC therapy for secondary stroke prevention compared the incidence of ischemic stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing medications (n=43), P-gp inducing medications (n=13), or no interacting medications (n=264). Twenty of the patients were on levetiracetam. There was no statistically significant difference between any of the groups.(7) A small prospective cohort study of 19 patients on the combination of levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4 patients on rivaroxaban) did not find a significant correlation between levetiracetam and DOAC concentrations. One patient who was on low-dose apixaban had low apixaban levels, and there were no thromboembolic events in the 1388 +/- 994 days of follow-up.(8)

Levetiracetam/Edoxaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Levetiracetam may decrease the efficacy of edoxaban.

CLINICAL EFFECTS: Concurrent use of levetiracetam may result in decreased effectiveness of edoxaban.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of levetiracetam in patients receiving edoxaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on edoxaban. If concurrent use is warranted, monitor patients closely for decreased response to edoxaban.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of 2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26 (1.13-4.54) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5) In a case report, a 54 year old man with a complicated medical history including paroxysmal atrial fibrillation, heart failure, and epilepsy who was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg twice daily, taken simultaneously with levetiracetam. On day 10 of dabigatran, trough levels were normal but Cmax was subtherapeutic. Separation of dabigatran administration to 4 hours before levetiracetam resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL. Over 32 months of follow-up, no hemorrhagic or ischemic events occurred.(6) A retrospective study of 320 patients with atrial fibrillation on DOAC therapy for secondary stroke prevention compared the incidence of ischemic stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing medications (n=43), P-gp inducing medications (n=13), or no interacting medications (n=264). Twenty of the patients were on levetiracetam. There was no statistically significant difference between any of the groups.(7) A small prospective cohort study of 19 patients on the combination of levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4 patients on rivaroxaban) did not find a significant correlation between levetiracetam and DOAC concentrations. One patient who was on low-dose apixaban had low apixaban levels, and there were no thromboembolic events in the 1388 +/- 994 days of follow-up.(8)

Levetiracetam/Rivaroxaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Levetiracetam may decrease the efficacy of rivaroxaban.

CLINICAL EFFECTS: Concurrent use of levetiracetam may result in decreased effectiveness of rivaroxaban.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of levetiracetam in patients receiving rivaroxaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on rivaroxaban. If concurrent use is warranted, monitor patients closely for decreased response to rivaroxaban.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of levetiracetam resulted in an odds ratio (95% CI) of 2.38 (1.19-4.75) and a propensity score adjusted odds ratio (95% CI) of 2.26 (1.13-4.54) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5) In a case report, a 69-year-old male on rivaroxaban for nonvalvular atrial fibrillation experienced transient ischemic attacks while on concurrent levetiracetam. During concurrent use of levetiracetam, rivaroxaban levels were subtherapeutic. After tapering off levetiracetam, rivaroxaban levels were within therapeutic range and the transient ischemic attacks resolved.(6) In a case report, a 54 year old man with a complicated medical history including paroxysmal atrial fibrillation, heart failure, and epilepsy who was on levetiracetam 500 mg twice daily was started on dabigatran 150 mg twice daily, taken simultaneously with levetiracetam. On day 10 of dabigatran, trough levels were normal but Cmax was subtherapeutic. Separation of dabigatran administration to 4 hours before levetiracetam resulted in an increase of Cmax from 88 ng/mL to 101 ng/mL. Over 32 months of follow-up, no hemorrhagic or ischemic events occurred.(7) A retrospective study of 320 patients with atrial fibrillation on DOAC therapy for secondary stroke prevention compared the incidence of ischemic stroke or TIA in patients on concomitant CYP3A4 and P-gp inducing medications (n=43), P-gp inducing medications (n=13), or no interacting medications (n=264). Twenty of the patients were on levetiracetam. There was no statistically significant difference between any of the groups.(8) A small prospective cohort study of 19 patients on the combination of levetiracetam and DOACs (8 patients on dabigatran, 9 patients on apixaban, 4 patients on rivaroxaban) did not find a significant correlation between levetiracetam and DOAC concentrations. One patient who was on low-dose apixaban had low apixaban levels, and there were no thromboembolic events in the 1388 +/- 994 days of follow-up.(9)

Levetiracetam is contraindicated in patients with known hypersensitivity to the drug.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 2 (mild) GFR 60-89 ml/min
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Depression
• Suicidal ideation

• Ataxia
• Gait abnormality
• Hallucinations
• Kidney disease with likely reduction in glomerular filtration rate (GFr)

Adverse effects occurring in 1% or more of adults receiving oral levetiracetam (as conventional preparations) for adjunctive management of partial seizures include somnolence, asthenia, headache, infection, dizziness, pain, pharyngitis, depression, nervousness, rhinitis, anorexia, ataxia, vertigo, amnesia, anxiety, emotional lability, hostility, paresthesia, increased cough, sinusitis, and diplopia.

Adverse effects occurring in 2% or more of pediatric patients older than 4 years of age receiving oral levetiracetam (as conventional preparations) for adjunctive management of partial seizures include headache, vomiting, nasopharyngitis, somnolence, fatigue, aggression, upper abdominal pain, cough, nasal congestion, decreased appetite, dizziness, pharyngolaryngeal pain, abnormal behavior, dizziness, irritability, diarrhea, lethargy, insomnia, head injury, anorexia, agitation, constipation, influenza, contusion, fall, depression, altered mood, ear pain, conjunctivitis, gastroenteritis, rhinitis, joint sprain, arthralgia, neck pain, sedation, labile affect, anxiety, confusional state, and mood swing. The most common adverse effects in patients younger than 4 years of age were somnolence and irritability.

The adverse effect profile of levetiracetam (as conventional preparations) in patients with myoclonic seizures or primary generalized tonic-clonic seizures is generally similar to that of patients with partial seizures.

Adverse effects occurring in 5% or more of patients receiving extended-release levetiracetam tablets for adjunctive management of partial seizures include influenza, somnolence, irritability, nasopharyngitis, dizziness, and nausea.

Adverse effects associated with IV levetiracetam generally appear to be consistent with those associated with oral administration of the drug.

More Frequent

• Infection

Less Frequent

• Hostility

Rare or Very Rare

• Abnormal hepatic function tests
• Acute hepatic failure
• Acute pancreatitis
• Acute renal failure
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Chorea
• DRESS syndrome
• Drug-induced psychosis
• Erythema multiforme
• Hallucinations
• Hepatitis
• Hyponatremia
• Leukopenia
• Neutropenic disorder
• Pancytopenia
• Panic disorder
• Rhabdomyolysis
• Skin rash
• Stevens-johnson syndrome
• Suicidal ideation
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Worsening of seizure

More Frequent

• Anorexia
• Dizziness
• Drowsy
• Eosinophilia
• Fatigue
• General weakness
• Headache disorder
• Irritability
• Nasal congestion
• Pharyngitis

Less Frequent

• Aggressive behavior
• Agitation
• Anemia
• Ataxia
• Constipation
• Cough
• Depersonalization
• Depression
• Diarrhea
• Diplopia
• Ecchymosis
• Hyperkinesis
• Indifference
• Influenza
• Insomnia
• Lymphocytosis
• Memory impairment
• Mood changes
• Neck pain
• Nervousness
• Pain
• Paresthesia
• Rhinitis
• Sinusitis
• Symptoms of anxiety
• Vertigo
• Vomiting

Rare or Very Rare

• Accidental fall
• Alopecia
• Behavioral disorders
• Blurred vision
• Disturbance of attention
• Dyskinesia
• Eczema
• Gastroenteritis
• Hypertension
• Muscle weakness
• Myalgia
• Obsessive-compulsive disorder
• Personality disorders
• Pruritus of skin
• Weight loss

No enhanced messaging available.

Safety and efficacy of levetiracetam immediate-release tablets, oral solution, and injection for the management of partial onset seizures have not been established in pediatric patients younger than 1 month of age. Behavioral abnormalities (e.g., paranoia, confusional state, increased aggression) have been observed in pediatric patients 4-16 years of age with partial onset seizures receiving the drug.

Safety and efficacy of levetiracetam immediate-release tablets, oral solution, and injection for the management of myoclonic seizures have not been established in pediatric patients younger than 12 years of age.

Safety and efficacy of levetiracetam immediate-release tablets, oral solution, and injection for the management of primary generalized tonic-clonic seizures have not been established in pediatric patients younger than 6 years of age.

Safety and efficacy of extended-release levetiracetam tablets have not been established in pediatric patients younger than 12 years of age. Use of the extended-release tablets in children 12 years of age and older is supported by a placebo-controlled study using the immediate-release preparation in patients 4-16 years of age.

Safety and efficacy of levetiracetam in sodium chloride injection have not been established in pediatric patients younger than 16 years of age.

Available data in pregnant women have not identified a drug-associated risk of major birth defects or miscarriage with levetiracetam. In animal reproduction studies, developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) was observed.

Seizure control during pregnancy should be carefully monitored; decreased plasma concentrations of levetiracetam may occur during pregnancy and dosage adjustments may be necessary to maintain clinical response.

A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to anticonvulsant drugs during pregnancy. Encourage women who are taking levetiracetam during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or https://www.aedpregnancyregistry.org.

Levetiracetam is distributed into human milk. It is not known whether the drug has any effects on the breastfed infant or on milk production. Consider the benefits of breastfeeding along with the mother's clinical need for levetiracetam and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Controlled clinical studies evaluating levetiracetam have not included sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. No substantial differences in safety have been observed in geriatric patients relative to younger adults.