Levetiracetam is a pyrrolidine with antiepileptic activity. The exact mechanism through which levetiracetam exerts its effects is unknown but does not involve inhibitory and excitatory neurotransmitter activity. Stereoselective binding of levetiracetam was confined to synaptic plasma membranes in the central nervous system with no binding occurring in peripheral tissue. Levetiracetam inhibits burst firing without affecting normal neuronal excitability, which suggests that it may selectively prevent hyper-synchronization of epileptiform burst firing and propagation of seizure activity.
Levetiracetam is a relatively unique anticonvulsant that is typically used in combination with other antiepileptic medications for partial-onset seizures. Levetiracetam has been linked to rare instances of serum aminotransferase and alkaline phosphatase elevations during treatment and too rare cases of clinically apparent drug-induced liver disease.
Levetiracetam is a pyrrolidinone and carboxamide that is N-methyl pyrrolidine-2-one in which one of the methyl hydrogens is replaced by an aminocarbonyl group, while another is replaced by an ethyl group (the S enantiomer). An anticonvulsant, it is used for the treatment of epilepsy in both human and veterinary medicine. It has a role as an anticonvulsant, an environmental contaminant and a xenobiotic.
Levetiracetam is a novel, antiepileptic drug used in the treatment of partial seizures, myoclonic seizures, and tonic-clonic seizures. In 2000, the FDA approved the use of the oral formulation as adjunctive therapy for the treatment of focal seizures, myoclonic seizures, and primary generalized seizures. The FDA approved intravenous levetiracetam in 2006 for use in patients older than 15 years, as adjunctive anticonvulsant therapy when the oral formulation is not tolerated. This activity covers levetiracetam, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, monitoring, and highlights the role of the interprofessional team in the management of conditions where levetiracetam therapy is helpful.
Mechanism of Action of Levetiracetam
The mechanisms by which LEV exerts its antiepileptic effects are not clearly defined. The most relevant mechanism of action is believed to be through binding to a unique protein known as synaptic vesicle protein 2A (SV2A). SV2A protein is a part of secretory vesicle membranes that mediates calcium-dependent vesicular neurotransmitter release. The binding of LEV to SV2A appears to decrease the rate of vesicle release.
The exact mechanism through which levetiracetam exerts its antiepileptic effects is unclear but is thought to be unique amongst other anti-epileptic medications. Current knowledge suggests that levetiracetam’s binding to synaptic vesicle protein 2A (SV2A) is a key driver of its action. SV2A is a membrane-bound protein that is found on synaptic vesicles and is ubiquitous throughout the CNS[A12546] – it appears to play a role in vesicle exocytosis[L8606, L8615] and in the modulation of synaptic transmission by increasing the available amount of secretory vesicles available for neurotransmission.[A12552] Stimulation of pre-synaptic SV2A by levetiracetam may inhibit neurotransmitter release,[A12551] but this action does not appear to affect normal neurotransmission. This has led to the suggestion that levetiracetam exclusively modulates the function of SV2A only under pathophysiological conditions.[A12546] Levetiracetam and related analogs showed a correlation between affinity for SV2A and anti-epileptic potency, further suggesting that action at this site contributes to the anti-epileptic activity of the drug.[L8606, L8615] Levetiracetam has also been shown to indirectly affect GABAergic neurotransmission (despite having no direct effect on GABAergic or glutamatergic receptors) and modulate ionic currents.[A12552] Similarly, levetiracetam has been shown in vitro to inhibit N-type calcium channels.[A16562] How, or even if, these actions are implicated in its anti-epileptic action have yet to be elucidated.
Indications of Levetiracetam
Levetiracetam is a novel, antiepileptic drug used in the treatment of partial seizures, myoclonic seizures, and tonic-clonic seizures. In 2000, the FDA approved the use of the oral formulation as adjunctive therapy for the treatment of focal seizures, myoclonic seizures, and primary generalized seizures. The FDA approved intravenous levetiracetam (LEV) in 2006 for use in patients older than 15 years, as adjunctive anticonvulsant therapy when the oral formulation is not tolerated. In Europe, it is approved for the treatment of partial seizures as a single agent and as an add-on treatment for partial seizures, tonic-clonic seizures, and myoclonic seizures.
It is chemically unrelated to other antiepileptic drugs. Its favorable safety profile, distinct mechanism of action, and fewer drug interactions make it an attractive therapeutic choice for the treatment of seizures.
Uses
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Myoclonic seizures – It is approved for use as adjunctive therapy in the treatment of myoclonic seizures in adults and juvenile myoclonic epilepsy in adolescents 12 years and older.
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Partial seizures – It can be used as adjunctive therapy for treating partial seizures in adults and children one month or older with epilepsy.
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Primary generalized tonic-clonic seizure – Used for adjunctive therapy for the treatment of primary generalized tonic conic seizure in adults and children more than 5 years old with idiopathic generalized epilepsy.
- Levetiracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults and children 4 years of age and older with epilepsy.
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Levetiracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures in epileptic patients who are one month of age and older. Additionally, it is indicated as an adjunct in the treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy who are 12 years of age and older, and in primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy who are 6 years of age and older.[L8606] Levetiracetam is also available as an orally dissolvable tablet that is indicated as an adjunct in the treatment of partial-onset seizures in patients with epilepsy who are 4 years of age and older and weigh more than 20kg.[L8609]
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Levetiracetam Actavis is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Actavis is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
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Levetiracetam Actavis Group is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Actavis Group is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from 1 month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
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Levetiracetam Hospira is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam Hospira is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents, and children from 4 years of age with epilepsy. in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy. in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy. Levetiracetam Hospira concentrate is an alternative for patients when oral administration is temporarily not feasible.
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Levetiracetam Ratiopharm is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Ratiopharm is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from 1 month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
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Levetiracetam is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
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Levetiracetam Teva is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam Teva is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents, children, and infants from 1 month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
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Keppra is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Keppra is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
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Mater is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Mater is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
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Levetiracetam Sun is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Sun is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults and children from four years of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy. Levetiracetam Sun concentrate is an alternative for patients when oral administration is temporarily not feasible.
Contraindications
- Hypersensitivity reaction to LEV or any component of the formulation.
- anemia
- decreased blood platelets
- low levels of white blood cells
- low levels of a type of white blood cell called neutrophils
- psychotic disorder
- suicidal thoughts
- depression
- hallucinations
- abnormal manner of walking
- loss of muscle coordination
- chronic kidney disease stage 2 (mild)
- chronic kidney disease stage 3A (moderate)
- chronic kidney disease stage 3B (moderate)
- chronic kidney disease stage 4 (severe)
- kidney disease with likely reduction in kidney function
Dosage of Levetiracetam
Strengths: 100 mg/mL; 250 mg; 500 mg; 750 mg; 1000 mg; 500 mg/100
Epilepsy
Immediate-Release
- Initial dose: 500 mg orally or IV twice a day
- Increase in increments of 500 mg twice a day every 2 weeks based on efficacy and tolerability
- Maintenance dose: 500 to 1500 mg orally or IV twice a day
- Maximum dose: 3000 mg/day
Extended-Release (Partial Onset Seizures Only)
- Initial dose: 1000 mg orally once a day
- Increase in increments of 1000 mg every 2 weeks based on efficacy and tolerability
- Maintenance dose: 1000 to 3000 mg orally once a day
- Maximum dose: 3000 mg/day
Seizures
Immediate-Release
- Initial dose: 500 mg orally or IV twice a day
- Increase in increments of 500 mg twice a day every 2 weeks based on efficacy and tolerability
- Maintenance dose: 500 to 1500 mg orally or IV twice a day
- Maximum dose: 3000 mg/day
Extended-Release (Partial Onset Seizures Only)
- Initial dose: 1000 mg orally once a day
- Increase in increments of 1000 mg every 2 weeks based on efficacy and tolerability
- Maintenance dose: 1000 to 3000 mg orally once a day
- Maximum dose: 3000 mg/day
Pediatric Dose for Epilepsy
PARTIAL ONSET SEIZURES:
Immediate-Release
1 month to less than 6 months
- Initial dose: 7 mg/kg oral/IV twice a day; increase in increments of 7 mg/kg twice a day in 2-week intervals
- Maximum dose: 21 mg/kg twice a day (clinical trials mean daily dose=35 mg/kg/day).
6 months to less than 4 years
- Initial dose: 10 mg/kg oral/IV twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
Maximum dose: 25 mg/kg twice a day; (clinical trials mean daily dose=47 mg/kg/day)
4 years to less than 16 years
- Initial dose: 10 mg/kg twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
- Maximum dose: 30 mg/kg twice a day (clinical trials mean daily dose=44 mg/kg/day)
Alternatively, 4 years to less than 16 years:
- weight 20 to 40 kg: 250 mg oral/IV twice a day, increase in increments of 250 mg twice a day in 2-week intervals; Maximum dose: 750 mg twice a day
- 4 years to less than 16 years: weight greater than 40 kg: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day\
- 16 years and older: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day
Extended-Release
12 years or older
- Initial dose: 1000 mg orally once a day
- Increase in increments of 1000 mg every 2 weeks to the maximum daily dose
- Maintenance dose: 1000 to 3000 mg orally once a day
- Maximum dose: 3000 mg/day
MYOCLONIC SEIZURES
12 years and older
- Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals
- Maintenance dose: 500 to 1500 mg twice a day
- Maximum dose of 3000 mg/day
PRIMARY GENERALIZED TONIC-CLONIC SEIZURES
6 years to less than 16 years
- Initial dose: 10 mg/kg oral/IV twice a day, increase in increments of 10 mg/kg twice a day in 2-week intervals
- Maximum dose: 30 mg/kg twice a day
16 years and older
- Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals
- Maximum dose: 1500 mg twice a day.
Seizures
PARTIAL ONSET SEIZURES
Immediate-Release
- 1 month to less than 6 months:
- Initial dose: 7 mg/kg oral/IV twice a day; increase in increments of 7 mg/kg twice a day in 2-week intervals
- Maximum dose: 21 mg/kg twice a day (clinical trials mean daily dose=35 mg/kg/day)
- 6 months to less than 4 years:
- Initial dose: 10 mg/kg oral/IV twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
- Maximum dose: 25 mg/kg twice a day; (clinical trials mean daily dose=47 mg/kg/day)
4 years to less than 16 years
- Initial dose: 10 mg/kg twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
- Maximum dose: 30 mg/kg twice a day (clinical trials mean daily dose=44 mg/kg/day)
Alternatively,
- 4 years to less than 16 years: weight 20 to 40 kg: 250 mg oral/IV twice a day, increase in increments of 250 mg twice a day in 2-week intervals; Maximum dose: 750 mg twice a day
- 4 years to less than 16 years: weight greater than 40 kg: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day
- 16 years and older: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day.
Extended-Release 12 years or older
- Initial dose: 1000 mg orally once a day
- Increase in increments of 1000 mg every 2 weeks to the maximum daily dose
- Maintenance dose: 1000 to 3000 mg orally once a day
- Maximum dose: 3000 mg/day.
MYOCLONIC SEIZURES
12 years and older:
- Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week interval
- Maintenance dose: 500 to 1500 mg twice a day
- Maximum dose of 3000 mg/day
PRIMARY GENERALIZED TONIC-CLONIC SEIZURES
6 years to less than 16 years
- Initial dose: 10 mg/kg oral/IV twice a day, increase in increments of 10 mg/kg twice a day in 2-week intervals
- Maximum dose: 30 mg/kg twice a day
16 years and older
- Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals
- Maximum dose: 1500 mg twice a day
- LEV is available in oral and intravenous (IV) formulations. Oral forms are available in immediate-release and extended-release forms.
Afterall
- The Minimum recommended dose is 500 mg twice daily. Some older adults may respond to doses as low as 500 mg per day. It should be started at a low dose and titrated up for a clinical response. Increase the dose at 250 or 500 mg at 1 to 2-week intervals until the clinical response is achieved. The maximum recommended dose is 3000 mg per day. Rapid dose escalation can lead to adverse effects. An immediate-release form is dosed twice daily and extended-release forms once daily. A therapeutic serum concentration is not established for LEV and dosage is guided by clinical response.
- Efficacy of more than 3000 mg/day dose is not fully established. Some suggest that dose can be increased up to 4000 mg /day in patients who have shown clear response but have occasional breakthrough seizures. There are some reports of seizure exacerbation with higher doses, and the physician should keep that in mind while using higher doses.
- The total daily dosage of IV LEV is equivalent to oral. It is administered as a 15-minute infusion. There is no evidence to use a loading dose.
- It is also used off-label sometimes for status epilepticus. The dose used is 1000 to 3000 mg IV infusion at a rate of 2 mg/kg per minute or a single dose of 60 mg/kg.
- LEV may be used safely (with caution) in children older than 4 years of age. The recommended starting dose is 20 mg/kg per day in 2 divided doses. It can be titrated up to 20 mg/kg every 2 weeks up to the maximum dose of 60 mg/kg per day.
Side Effects of Levetiracetam
The Most Common
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Central nervous system (CNS) – Most common side effects are neurobehavioral like somnolence, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, the decline in cognition and increased suicide risk. Most of the time side effects are mild. About 1% of patients experience serious side effects like psychosis, hallucinations and suicidal thoughts. These side effects are more common in the first month of treatment but can develop any time during treatment and improve once the drug is discontinued. Dose reduction is associated with improvement in behavioral problems.
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Cardiovascular (CVS) – Increased diastolic blood pressure in infants and children
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Gastrointestinal (GI) – Vomiting, abdominal pain, nausea, anorexia
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Infections – Pharyngitis, rhinitis has been reported in 7% to 15% of patients.
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Hypersensitivity reactions – Rarely, serious, life-threatening reactions have been reported with the use of LEV. These include angioedema, anaphylaxis, Steven-Johnson syndrome, toxic epidermal necrolysis, hives, respiratory distress.
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Hematologic – Leukopenia, eosinophilia, and rarely pancytopenia have been reported with the use of LEV.
Common
- unusual changes in mood or behavior (unusual risk-taking behavior, being irritable or talkative);
- confusion, hallucinations, loss of balance or coordination;
- extreme drowsiness, feeling very weak or tired;
- problems with walking or movement;
- a skin rash, no matter how mild;
- easy bruising, unusual bleeding; or
- fever, chills, weakness, or other signs of infection.
- dizziness, drowsiness, tiredness;
- weakness;
- feeling aggressive or irritable
- loss of appetite;
- stuffy nose; or
- infection.
Less common
- Bloody nose
- burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
- clumsiness or unsteadiness
- discouragement
- dizziness or lightheadedness
- double vision
- earache
- feeling of constant movement of self or surroundings
- feeling sad or empty
- increase in body movements
- loss of bladder control
- loss of memory
- mood or mental changes
- outburst of anger
- pain or tenderness around the eyes and cheekbones
- problems with memory
- redness or swelling in the ear
- seizures
- sensation of spinning
- shakiness and unsteady walk
- shakiness in the legs, arms, hands, or feet
- tightness of the chest
- trembling or shaking of the hands or feet
- trouble concentrating
- unsteadiness, trembling, or other problems with muscle control or coordination
Drug Interactions of Levetiracetam
No significant drug interactions of LEV are observed with other anti-epileptics like phenytoin, valproic acid, carbamazepine, phenobarbital, primidone. No significant interactions with drugs like digoxin or warfarin.
LEV metabolism rate and its clearance may be increased in patients taking enzyme-inducing anti-epileptics like phenytoin, carbamazepine, and phenobarbital.
- Aspirin Low Strength (aspirin)
- Aspirin Low Strength (aspirin)
- Fish Oil (omega-3 polyunsaturated fatty acids)
- Fish Oil (omega-3 polyunsaturated fatty acids)
- Lyrica (pregabalin)
- Lyrica (pregabalin)
- Metoprolol Succinate ER (metoprolol)
- Metoprolol Succinate ER (metoprolol)
- Metoprolol Tartrate (metoprolol)
- Metoprolol Tartrate (metoprolol)
- MiraLAX (polyethylene glycol 3350)
- MiraLAX (polyethylene glycol 3350)
- Tylenol (acetaminophen)
- Tylenol (acetaminophen)
- Vitamin B12 (cyanocobalamin)
- Vitamin B12 (cyanocobalamin)
- Vitamin C (ascorbic acid)
- Vitamin C (ascorbic acid)
- Vitamin D3 (cholecalciferol)
- Vitamin D3 (cholecalciferol)
Since LEV can cause somnolence and CNS depression, it may enhance the CNS-depressant effect of alcohol, cannabis, and other drugs like azelastine, carbamazepine, opioids, among others.[rx][rx][rx][rx][rx]
Pregnancy Category of Levetiracetam
Pregnancy
LEV is a pregnancy category C drug. Maternal serum levels can fall significantly during the third trimester, and monitoring of serum concentration should be used to guide dosing. No significant congenital abnormalities have been reported following maternal use of LEV. It is excreted in breast milk, but serum drug levels in infants have been shown to below. [rx][rx][rx]
Monitoring
Baseline creatinine should be checked before initiating LEV therapy. Signs and symptoms of depression, suicidality, and psychosis should be closely monitored. Blood pressure should be monitored closely in children less than 4 years old.
Generally, no blood monitoring is required during therapy. Serum concentrations may help assess compliance and may be used as a dosing guide in pregnant and elderly patients.[rx]
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