Levetiracetam - Indication, Dosage, Precautions, and Contraindications

Overview

Levetiracetam, a new antiepileptic drug, is used to treat various seizures, including partial, myoclonic, and tonic-clonic seizures. The FDA (Food and Drug Administration) approved its oral use in 2000 as an additional treatment for focal seizures, myoclonic seizures, and primary generalized seizures. In 2006, the FDA also approved intravenous Levetiracetam for patients over 15 years old when the oral form was not suitable. This overview includes details about Levetiracetam's mechanism of action, how it works in the body, potential side effects, who it can benefit, and monitoring aspects. Despite being chemically different from other antiepileptic drugs, Levetiracetam stands out for its safety, unique working method, and minimal interactions with other medications, making it a promising option for managing seizures.

Drug Group

Levetiracetam is a medication used to treat epilepsy and comes in tablet form (250 mg (milligram), 500 mg, 750 mg, and 1000 mg) as well as a liquid form (100 mg/mL (milligram per milliliter)) for oral use. The tablets have different colors: blue, yellow, orange, and white. The active ingredient in Levetiracetam drug formulation is Levetiracetam, a chemical with the molecular formula C8H14N2O2 and a molecular weight of 170.21g/mol (gram per molecule). It is a unique compound not related to other epilepsy drugs, and its chemical structure is represented by a specific formula.

Available Doses and Dosage Forms:

Levetiracetam Tablets:

1. Levetiracetam 250 mg: Blue, oblong, scored tablets marked "ucb 250," supplied in white bottles (120 tablets).

2. Levetiracetam 500 mg: Yellow, oblong, scored tablets marked "ucb 500," supplied in white bottles (120 tablets).

3. Levetiracetam 750 mg: Orange, oblong, scored tablets marked "ucb 750," supplied in white bottles (120 tablets).

4. Levetiracetam 1000 mg: White, oblong, scored tablets marked "ucb 1000," supplied in white bottles (60 tablets).

Levetiracetam Oral Solution:

1. Grape-flavored liquid with a concentration of 100 mg/mL.

For Patients

What Is Epilepsy?

Epilepsy is a brain disorder marked by recurrent seizures, which are sudden changes in behavior caused by temporary shifts in the brain's electrical activity. Normally, the brain sends out small electrical impulses in an organized way, traveling through nerve cells and the body with the help of chemical messengers. In epilepsy, these electrical rhythms can become unbalanced, leading to repeated seizures. Diagnosis typically occurs after experiencing at least two seizures unrelated to known medical conditions. Seizures can manifest differently based on the specific brain area affected. For instance, if a seizure originates in the part of the brain controlling thumb movement, it may start with jerking in the opposite thumb or hand, as the right brain governs the left side of the body and vice versa.

How Does Levetiracetam Work?

Levetiracetam is a medication used to treat specific types of epilepsy. Seizures are like sudden bursts of electrical activity in the brain, and Levetiracetam helps slow down these signals to prevent seizures. While the exact way it works is not fully understood, experts believe it helps calm down excessive nerve activity and lessens the spread of seizures, possibly by affecting pathways related to calcium, glycine, and GABA (gamma-aminobutyric acid). It falls under the category of drugs called anticonvulsants.

What Is the Dosage of Levetiracetam?

Levetiracetam is a powdered medication that comes in white to an off-white color, with a subtle odor and bitter taste. It dissolves well in water, chloroform, and methanol, moderately in ethanol, less in acetonitrile, and hardly at all in n-hexane. Levetiracetam tablets contain the specified amount of the medication along with other ingredients, including colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, polyethylene glycol 3350, polyethylene glycol 6000, polyvinyl alcohol, talc, titanium dioxide, and additional agents depending on the tablet strength (250 mg, 500 mg, or 750 mg). The oral solution of Levetiracetam has 100 mg of the medication in each milliliter, and its inactive components include ammonium glycyrrhizinate, citric acid monohydrate, glycerin, maltitol solution, methylparaben, potassium acesulfame, propylparaben, purified water, sodium citrate dihydrate, and natural and artificial flavoring.

What Are the Things to Inform the Doctor Before Taking the Drug?

• Inform the doctor and pharmacist about any allergies to Levetiracetam or its components.

• Share details about all medications, including prescriptions, over-the-counter drugs, vitamins, supplements, and herbs.

• Disclose any history of kidney disease, depression, mood problems, or suicidal thoughts to the doctor.

• Notify the doctor if the person is pregnant, planning pregnancy, or breastfeeding.

• Be cautious of potential dizziness or drowsiness caused by Levetiracetam; avoid driving or operating machinery until understanding its effects.

• Recognize that mental health may change unexpectedly, including experiencing suicidal thoughts.

• Contact the doctor immediately if symptoms like panic attacks, restlessness, aggression, or thoughts of self-harm are noticed.

• Collaborate with the doctor to assess risks and benefits and determine the most suitable treatment plan.

• Ensure the family is aware of the serious symptoms requiring prompt medical attention.

How Is Levetiracetam Administered?

1. Partial Onset Seizures in Adults (16 Years and Older): Start with a daily dose of 1000 mg (milligram), given as 500 mg twice daily (BID). Adjust by adding 1000 mg/day every two weeks, reaching a maximum of 3000 mg/day. Higher doses do not consistently show increased benefits.

2. Pediatric Patients (Four to Less Than 16 Years) For Partial Onset Seizures: Initiate with 20 mg/kg (milligram per kilogram) in two divided doses (10 mg/kg BID). Increase every two weeks by 20 mg/kg, up to the recommended 60 mg/kg/day. Tablets or oral solutions can be used based on weight. A calibrated measuring device is essential.

3. Myoclonic Seizures in Patients 12 Years and Older With Juvenile Myoclonic Epilepsy: Start with 1000 mg/day, given as 500 mg BID. Increase by 1000 mg/day every two weeks, up to 3000 mg/day. Effectiveness below 3000 mg/day is unknown.

4. Primary Generalized Tonic-Clonic Seizures: Adults (16 Years and Older) must be initiated with 1000 mg/day, given as 500 mg BID. Increase by 1000 mg/day every two weeks, up to 3000 mg/day. Effectiveness below 3000 mg/day is unclear. Pediatric Patients (six to less than 16 Years) should follow a similar dosing pattern, starting with 20 mg/kg.

5. Adult Patients With Impaired Renal Function: Adjust Levetiracetam dosing according to the physician’s advice on renal function. Dosage adjustments are essential for patients with impaired renal function to ensure safety and effectiveness.

What Are the Side Effects of Levetiracetam?

• Adverse event incidence figures provided for Levetiracetam, when added to concurrent antiepileptic drug therapy, may not accurately predict occurrence in real-world medical practice.

• Prescribers can use these figures as a basis to estimate the relative contribution of drug and non-drug factors to adverse event incidences in the studied population.

• For partial onset seizures in adults, common adverse events with Levetiracetam combined with other drugs include somnolence (sleepiness), asthenia (weakness), infection, and dizziness. Common events in pediatric patients (four to 16 years) include somnolence, accidental injury, hostility, nervousness, and asthenia.

• For myoclonic seizures, common adverse events in both adolescents and adults include somnolence, neck pain, and pharyngitis (inflammation of the pharynx).

• For primary generalized tonic-clonic seizures, the most frequent adverse event in patients (four years and older) is nasopharyngitis (common cold).

• The time course of onset for adverse events in partial-onset seizures, asthenia, somnolence, and dizziness predominantly occurs within the first four weeks of Levetiracetam treatment.

• Discontinuation or dose reduction due to adverse events, in well-controlled studies for partial onset seizures, 15.0 percent of adults on Levetiracetam and 11.6 percent on placebo discontinued or reduced doses due to adverse events. In pediatric studies for partial-onset seizures, the rates were 16.8 percent for Levetiracetam and 20.6 percent for placebo. For myoclonic seizures, 8.3 percent on Levetiracetam and 1.7 percent on placebo discontinued or reduced dose. For primary generalized tonic-clonic seizures, 5.1 percent on Levetiracetam and 8.3 percent on placebo discontinued or reduced dose.

• Overall, the adverse experience profile was similar between females and males; there was insufficient data for age and race distributions.

• Postmarketing experiences reported include abnormal liver function, hepatic failure (liver failure), hepatitis (inflammation of liver), leukopenia (decrease in number of white blood cells in blood), neutropenia (decrease in number of neutrophils in blood), pancreatitis (inflammation of pancreas), pancytopenia (low level of red blood cells, white blood cells and platelets), thrombocytopenia (low blood platelet count) and weight loss. Alopecia (hair loss) was observed in some cases, with recovery upon Levetiracetam discontinuation. Incidence and causation are unclear.

Dietary Considerations

Keep having a regular diet unless the doctor advises differently.

Missed Dose

If a person forgets to take their medication and it has been just a few hours since the scheduled dose, they take it as soon as they remember. But if it is almost time for the next dose, just skip the missed one and stick to the usual schedule. Do not take extra to compensate for the missed dose.

Overdose

• Overdose symptoms of Levetiracetam in humans are not well-documented, but the highest known dose in clinical trials was 6000 mg/day.

• Few cases of overdose in clinical trials showed only drowsiness as an adverse event.

• Post-marketing cases reported symptoms like somnolence, agitation, aggression, decreased consciousness, respiratory depression (slow and shallow breathing), and coma (unconsciousness and lack of response to stimuli).

• No specific antidote for Levetiracetam overdose exists. If needed, attempts to eliminate unabsorbed drugs may include inducing vomiting or gastric lavage, while maintaining airway precautions.

• General supportive care, vital signs monitoring, and observation of the patient's clinical status are recommended. Consult a Poison control center for updated guidance on managing Levetiracetam overdose.

• Hemodialysis (a machine that filters wastes, salts, and fluid from the blood when kidneys no longer work), though not performed in known cases, may be considered for significant clearance of the drug in cases of overdose, especially in patients with renal impairment.

Storage:

Keep Levetiracetam at room temperature, around 77 degrees Fahrenheit (25 degrees Celsius), with short excursions allowed between 59 to 86 degrees Fahrenheit (15 to 30 degrees Celsius).

For Doctors

Indications:

• Levetiracetam is prescribed as an adjunctive therapy for partial-onset seizures in adults and children (four years and older) with epilepsy.

• It is indicated as an adjunctive therapy for myoclonic seizures in adults and adolescents (12 years and older) diagnosed with juvenile myoclonic epilepsy.

• Levetiracetam is recommended as adjunctive therapy for primary generalized tonic-clonic seizures in adults and children (six years and older) with idiopathic generalized epilepsy.

• Off-label uses include treatment for status epilepticus and seizure prophylaxis in subarachnoid hemorrhage.

• It is also utilized off-label for the prophylaxis of traumatic brain injury and supratentorial neurosurgery.

• Levetiracetam is employed off-label for managing seizures in palliative care.

Dose:

Levetiracetam is a crystalline powder with a white to off-white color, a subtle odor, and a bitter taste. It has high solubility in water (104.0 g (gram)/100 mL), chloroform, and methanol, moderate solubility in ethanol, low solubility in acetonitrile, and is nearly insoluble in n-hexane. The Levetiracetam tablets contain the specified amount of Levetiracetam along with inactive components, including colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, polyethylene glycol 3350, polyethylene glycol 6000, polyvinyl alcohol, talc, titanium dioxide, and additional agents that vary based on the tablet strength (250 mg, 500 mg, or 750 mg). The Levetiracetam oral solution has 100 mg of Levetiracetam per mL (milliliter) and includes inactive ingredients such as ammonium glycyrrhizinate, citric acid monohydrate, glycerin, maltitol solution, methylparaben, potassium acesulfame, propylparaben, purified water, sodium citrate dihydrate, and natural and artificial flavoring.

Dosing Considerations:

• Levetiracetam is recommended as an adjunctive treatment for partial-onset seizures in adults and children aged four years and older with epilepsy.

• It is also indicated as adjunctive therapy for managing myoclonic seizures in adults and adolescents aged 12 years and older diagnosed with juvenile myoclonic epilepsy.

• Levetiracetam is indicated as adjunctive therapy for treating primary generalized tonic-clonic seizures in adults and children aged six years and older with idiopathic generalized epilepsy.

Pharmacological Aspects of Levetiracetam

• Pharmacodynamics: The impact of Levetiracetam on the prolongation of QTc interval was assessed in a controlled crossover study involving 52 healthy subjects. The study included both positive control (Moxifloxacin 400 mg) and placebo groups, with Levetiracetam administered at doses of 1000 mg or 5000 mg. The results indicated that the upper limit of the 90 percent confidence interval for the largest placebo-adjusted, baseline-corrected QTc did not exceed 10 milliseconds. Therefore, there was no significant evidence of QTc prolongation associated with Levetiracetam in this investigation.

• Mechanism of Action: The exact mechanism of Levetiracetam's antiepileptic effects is unclear. The drug showed limited impact on single seizures induced by various stimuli but demonstrated protective effects against secondarily generalized activity from focal seizures and inhibitory properties in the kindling model. In both in vitro and in vivo studies, Levetiracetam inhibited hippocampal burst firing without affecting normal neuronal excitability, suggesting it may selectively prevent hypersynchronization of epileptiform burst firing and seizure spread. Levetiracetam, up to 10 μM (micromoles) concentrations, lacked binding affinity for known epilepsy-associated receptors and did not directly affect neuronal sodium or calcium currents. However, it opposed negative modulators of GABA (gamma-aminobutyric acid)- and glycine-gated currents and partially inhibited N-type calcium currents. Experimental data identified a saturable binding site for Levetiracetam in rat brain tissue as the synaptic vesicle protein SV2A (synaptic vesicle glycoprotein), involved in vesicle exocytosis regulation. While the molecular significance remains unclear, Levetiracetam's affinity for SV2A and related analogs correlated with their antiseizure potency in mice, suggesting a potential contribution to its antiepileptic mechanism.

• Pharmacokinetics: Levetiracetam's pharmacokinetics were studied in various populations, including healthy adults, epilepsy patients (adults and children), the elderly, and those with renal or hepatic impairment. The drug is rapidly absorbed orally, with linear and time-invariant pharmacokinetics and low variability. Bioequivalence exists between tablets and oral solution, and bioavailability is unaffected by food, with minimal protein binding (less than 10 percent). About 66 percent of the dose is renally excreted unchanged. Levetiracetam's major metabolic pathway (24 percent of dose) involves enzymatic hydrolysis, independent of liver cytochrome P450. Metabolites lack pharmacological activity and are renally excreted. Plasma half-life is six to eight hours, increased in the elderly and those with renal impairment due to reduced clearance. Absorption is rapid, with peak concentrations reached in about an hour. Oral bioavailability is 100 percent, and pharmacokinetics remain linear across a dose range of 500-5000 mg (milligram), achieving steady state after two days of twice-daily dosing. Food decreases peak concentration by 20 percent and delays time to peak concentration by 1.5 hours. Minimal metabolism occurs in humans, primarily through enzymatic hydrolysis. The major metabolite, ucb L057, is inactive in seizure models. Elimination is mainly through renal excretion, with 66 percent unchanged drug. Clearance correlates with creatinine clearance, and renal clearance of ucb L057 involves glomerular filtration and active tubular secretion.

In adults, plasma half-life is seven ± one hour, unaffected by dose or repeated administration. Total body clearance is 0.96 mL/min/kg (milliliter per minute per kilogram), with renal clearance at 0.6 mL/min/kg. Excretion involves glomerular filtration and partial tubular reabsorption, and the metabolite ucb L057 is excreted via glomerular filtration and active tubular secretion, with a renal clearance of four mL/min/kg. Clearance is reduced in renal impairment.

Clinical Studies:

Levetiracetam's efficacy as adjunctive therapy for refractory partial onset seizures in adults was assessed in three placebo-controlled studies. These studies involved 904 patients randomized to receive placebo or different doses of Levetiracetam (1000 mg, 2000 mg, or 3000 mg/day). The trials demonstrated a statistically significant reduction in weekly partial seizure frequency compared to placebo, with a primary focus on achieving a ≥ 50 percent reduction.

Study one, conducted in the U.S. (United States), showed that both 1000 mg/day and 3000 mg/day of Levetiracetam led to a significant reduction in seizure frequency compared to placebo. Study two, carried out in Europe, revealed a statistically significant difference in responder rates between the 2000 mg/day and 1000 mg/day doses. Study three, also in Europe, demonstrated a significant reduction in seizure frequency with 3000 mg/day compared to placebo.

The results, presented graphically, highlight the percentage of patients achieving a ≥ 50 percent reduction in weekly seizure rates for each treatment group. These findings underscore Levetiracetam's effectiveness in reducing seizure frequency in adults with refractory partial-onset seizures.

What Are the Contraindications of Levetiracetam?

• Hypersensitivity reaction to Levetiracetam or its excipients is a contraindication.

• Levetiracetam use can lead to anaphylaxis or angioedema.

• If a hypersensitivity reaction occurs and an alternative cause cannot be determined, discontinuation of Levetiracetam should be permanent.

Warnings and Precautions:

• Antiepileptic drugs (AEDs), including Levetiracetam, elevate the risk of suicidal thoughts or behavior in patients across all indications.

• Patients using any AED should be closely monitored for the emergence or worsening of depression, suicidal thoughts, behavior changes, or unusual mood changes.

• Pooled analyses of 199 placebo-controlled clinical trials involving eleven AEDs revealed that patients on AEDs had approximately twice the risk of suicidal thinking or behavior compared to those on placebo.

• The estimated incidence rate of suicidal behavior or ideation among AED-treated patients was 0.43 percent, compared to 0.24 percent among placebo-treated patients.

• The increased risk was observed as early as one week into AED treatment and persisted throughout the assessed duration.

• Data analysis indicated a consistent risk of suicidal thoughts or behavior across AEDs with varying mechanisms of action and indications.

• Based on clinical trials, the risk did not significantly vary by age (five to 100 years).

• Suicidal risk was observed for all AEDs used for any indication, with a relatively small number of suicides reported in drug-treated patients.

What Are the Drug Interactions of Levetiracetam?

Due to its potential to induce sedation and central nervous system (CNS) depression, Levetiracetam may amplify the CNS-depressant effects of substances like alcohol, cannabis, and certain drugs, including Azelastine, Carbamazepine, and Opioids. Concurrent use with enzyme-inducing antiepileptic drugs, such as Phenytoin and Carbamazepine, led to a nine to 22 percent increase in Levetiracetam clearance. Conversely, co-administration with enzyme-inhibitor drugs like Valproate resulted in an 18.8 percent reduction in Levetiracetam clearance.

Specific Considerations:

1. Pregnancy: Levetiracetam levels may decrease during pregnancy. There might be potential risks to the fetus. Animal studies showed developmental issues at doses similar to or greater than human therapeutic doses. Use during pregnancy only if potential benefits outweigh potential risks.

2. Labor and Delivery: Unknown effects of Levetiracetam on labor and delivery in humans.

3. Nursing Mothers: Levetiracetam is present in human milk. Considering the potential risks to nursing infants, a decision should be made to discontinue nursing or the drug.

4. Pediatric Use: Levetiracetam’s safety and effectiveness are established in various pediatric age groups for specific seizure types. Neurocognitive and behavioral effects were studied in pediatric patients; no formal statistical non-inferiority was assessed. Studies in juvenile animals did not indicate age-specific toxicity.

5. Geriatric Use: No overall safety differences were observed between elderly and younger subjects. Elderly patients may have decreased renal function, so dose selection should be careful.

6. Renal Impairment: Levetiracetam clearance is reduced in patients with renal impairment. Dose adjustment is recommended for those with impaired renal function, and supplemental doses may be needed after dialysis.