Levetiracetam

Levetiracetam, sold under the brand name Keppra among others, is an antiepileptic drug<ref name=Kumar.2023>Template:Cite book</ref> (medication) used to treat epilepsy.<ref name=AHFS2019/> It is used for partial-onset, myoclonic, or tonic–clonic seizures,<ref name=Kumar.2023/> and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.<ref name=AHFS2019/>

Common side effects of levetiracetam include sleepiness, dizziness, feeling tired, and aggression.<ref name=AHFS2019>Template:Cite web</ref> Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens–Johnson syndrome or anaphylaxis.<ref name=AHFS2019/> Levetiracetam is the S-enantiomer of etiracetam.<ref>Template:Cite book</ref> It acts as a synaptic vesicle glycoprotein 2A (SV2A) ligand.<ref name="WuCaoTian2024">Template:Cite journal</ref>

Levetiracetam was approved for medical use in the United States in 1999<ref name=AHFS2019/> and is available as a generic medication.<ref name=BNF76>Template:Cite book</ref> In 2023, it was the 101st most commonly prescribed medication in the United States, with more than 6Template:Nbspmillion prescriptions.<ref name="Top300Drugs">Template:Cite web</ref><ref>Template:Cite web</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref>

Medical uses

Focal epilepsy

Levetiracetam is effective as single-drug treatment for newly diagnosed focal epilepsy in adults.<ref>Template:Cite journal</ref><ref name="Cochrane_2022">Template:Cite journal</ref> It reduces focal seizures by 50% or more as an add-on medication.<ref name="Mbizvo"/>

Partial-complex epilepsy

Levetiracetam is effective as add-on treatment for partial (focal) epilepsy.<ref>Template:Cite journal</ref>

Generalized epilepsy

Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy.<ref name ="Cochrane_2022" /> It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures.<ref name="Keppra tablet FDA label" /> Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures or as an adjunctive therapy for partial, myoclonic, and tonic-clonic seizures.<ref>Template:Cite book</ref>

Levetiracetam is sometimes used off label to treat status epilepticus.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Prevention of seizures

Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury.<ref>Template:Cite journal</ref> It may be effective for prevention of seizures associated with subarachnoid hemorrhages.<ref>Template:Cite journal</ref>

Other

Levetiracetam has not been found to be useful for treatment of neuropathic pain,<ref>Template:Cite journal</ref> nor for treatment of essential tremors.<ref>Template:Cite journal</ref> Levetiracetam has not been found to be useful for treating all developmental disorders within the autism spectrum;<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> studies have only proven to be an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.<ref>Template:Cite journal</ref>

Special groups

Levetiracetam's efficacy and tolerability in individuals with intellectual disability is comparable to those without.<ref>Template:Cite journal</ref>

Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.Template:Medical citation needed

Studies were conducted to look for increased adverse effects in the elderly population as compared to younger patients. One such study published in Epilepsy Research showed no significant increase in incidence of adverse symptoms experienced by young or elderly patients with disorders of the central nervous system.Template:Medical citation needed

Levetiracetam is the most commonly prescribed initial antiepileptic in infants who are between the ages of 1-36 months old. One study found 66% of participants to be seizure free after an average of 12 months on levetiracetam, a relatively high percentage compared to other antiepileptics.<ref name="Treadwell_2022" />

Adverse effects

The most common adverse effects of levetiracetam treatment include effects on the central nervous system such as somnolence, decreased energy, headache, dizziness, mood swings and coordination difficulties. These adverse effects are most pronounced in the first month of therapy. About 4% of patients dropped out of pre-approval clinical trials due to these side effects.<ref name="Keppra tablet FDA label" />

About 13% of people taking levetiracetam experience adverse neuropsychiatric symptoms, which are usually mild. These include agitation, hostility, apathy, anxiety, emotional lability, and depression. Serious psychiatric adverse side effects that are reversed by drug discontinuation occur in about 1%. These include hallucinations, suicidal thoughts, or psychosis. These occur mostly within the first month of therapy, but can rarely develop at any time during treatment.<ref name="pmid18728811">Template:Cite journal</ref>

Although rare, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which appears as a painful spreading rash with redness and blistering and/or peeling skin, have been reported in patients treated with levetiracetam.<ref>Template:Cite journal</ref> The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.<ref>Template:Cite journal</ref>

Levetiracetam should not be used in people who have previously shown hypersensitivity to levetiracetam or any of the inactive ingredients in the tablet or oral solution. Such hypersensitivity reactions include, but are not limited to, unexplained rash with redness or blistered skin, difficulty breathing, and tightness in the chest or airways.<ref name="Keppra tablet FDA label" />

In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than for those on different epileptic medications.<ref name="pmid22541979">Template:Cite journal</ref>

Suicide

Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicidal behavior or thoughts. Patients taking levetiracetam should be monitored closely for signs of worsening depression, suicidal thoughts or tendencies, or any altered emotional or behavioral states.<ref name="Keppra tablet FDA label">Template:Cite web</ref>

Kidney and liver

Kidney impairment decreases the rate of elimination of levetiracetam from the body. Individuals with reduced kidney function may require dose adjustments, guided by monitoring of kidney function.<ref name="Keppra tablet FDA label" />

Dose adjustment of levetiracetam is not necessary in liver impairment.<ref name="Keppra tablet FDA label" />

Drug interactions

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.<ref>Template:Cite journal</ref> The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.<ref>Template:Cite journal</ref>

Mechanism of action

The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. Levetiracetam does not exhibit pharmacologic actions similar to that of classical anticonvulsants. It does not inhibit voltage-dependent Na+ channels, does not affect GABAergic transmission, and does not bind to GABAergic or glutamatergic receptors.<ref>Template:Cite journal</ref> However, the drug binds to SV2A,<ref name="Lynch">Template:Cite journal</ref> a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels,<ref name="Vogl">Template:Cite journal</ref> reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.<ref name="Rogawski">Template:Cite journal</ref> As of 2024, this is widely accepted to be its mechanism of action.<ref name="WuCaoTian2024" /> However, the molecular basis of this action remains unknown.<ref name="WuCaoTian2024" />

Pharmacokinetics

The FDA provided a detailed review of the pharmacology and biopharmaceutics of Levetiracetam in 2013.<ref name=FDA-2013-review>Template:Cite report</ref>

Absorption

The absorption of levetiracetam tablets and oral solution is rapid and essentially complete. The bioavailability of levetiracetam is close to 100 percent, and the effect of food on absorption is minor.<ref name="Keppra tablet FDA label" />

Distribution

The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).<ref name="Keppra tablet FDA label" />

Metabolism

Levetiracetam does not undergo extensive metabolism, and the metabolites formed are not active and do not exert pharmacological activity. Metabolism of levetiracetam is not by liver cytochrome P450 enzymes, but through other metabolic pathways such as hydrolysis and hydroxylation.<ref name="Keppra tablet FDA label" />

Excretion

In persons with normal kidney function, levetiracetam is eliminated from the body primarily by the kidneys with about 66 percent of the original drug passed unchanged into urine. The plasma half-life of levetiracetam in adults is about 6 to 8 hours,<ref name="Keppra tablet FDA label" /> although the mean CSF half life of approx. 24 hours better reflects levels at site of action.<ref>Template:Cite journal</ref>

Analogues

Brivaracetam, a chemical analogue to levetiracetam, is a racetam derivative with similar properties.

Society and culture

Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.<ref>Template:Cite web</ref>

The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011.<ref>Template:Cite web</ref><ref name="Mbizvo">Template:Cite journal</ref> The patent for the extended release tablet will expire in 2028.<ref>Template:Cite web</ref>

The branded version Keppra is manufactured by UCB Pharmaceuticals S.A.<ref name="Keppra SmPC" /><ref name="Keppra tablet FDA label" /><ref name="Keppra XR FDA label" /><ref name="Keppra IV FDA label" />

In 2015, Aprecia's orally disintegrating tablet form of the drug manufactured using pharmaceutical 3D printing techniques was approved by the FDA, under the trade name Spritam.<ref>Template:Cite web</ref> Some have said that the drug has been improved by 3D printing, as the formula used now has improved disintegration properties.<ref>Template:Cite journal</ref>

Legal status

Australia

Levetiracetam is a Schedule 4 substance in Australia under the Poisons Standard (February 2020).<ref name="Poisons Stanrard">Poisons Standard February 2020 Template:Webarchive. comlaw.gov.au</ref> A Schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."<ref name="Poisons Stanrard" />

Japan

Under Japanese law, levetiracetam and other racetams cannot be brought into the country except for personal use by a traveler for whom it has been prescribed.<ref>Template:Cite web</ref> Travelers who plan to bring more than a month's worth must apply for an import certificate, known as a Template:Nihongo.<ref>Template:Cite web</ref>

Research

Levetiracetam has been studied in the past for treating symptoms of neurobiological conditions such as Tourette syndrome,<ref>Template:Cite journal</ref> and anxiety disorder.<ref name="Farooq">Template:Cite journal</ref> However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.<ref name="Farooq" />

Levetiracetam is being tested as a drug to reduce hyperactivity in the hippocampus in Alzheimer's disease.<ref>Template:Cite journal</ref>

Additionally, levetiracetam has been experimentally shown to reduce levodopa-induced dyskinesia,<ref>Template:Cite journal</ref> a type of movement disorder, or dyskinesia associated with the use of levodopa, a medication used to treat Parkinson's disease.

Many antiepileptic drugs cause changes in basic EEG activity. These include, in particular, carbamazepine, benzodiazepines, and phenobarbital. However, the effect of levetiracetam on basic EEG activity is minimal; no measurable increase in drug-induced beta activity was observed. At the same time, a significant reduction in seizure-like EEG abnormalities was observed.<ref>Template:Cite book</ref>

Of the ten medications evaluated in a 2023 systematic review of the literature, levetiracetam was found to be the only medication with sufficient evidence showing that it may cause seizure freedom in some infants.<ref name="Treadwell_2022">Template:Cite report</ref> Further, adverse effects from levetiracetam were rarely severe enough for the medication to be discontinued in this age group. Because available research included only two published studies reporting seizure freedom rates, however, the strength of the evidence was judged to be low.<ref name="Treadwell_2022" />

History

Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice.<ref name="LEV-discovered-1992"> Template:Cite journal</ref>