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levetiracetam

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levetiracetam
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{{Drugbox| Verifiedfields = changed| Watchedfields = changed| verifiedrevid = 419931567| drug_name = | IUPAC_name = (S)-2-(2-Oxopyrrolidin-1-yl)butanamide| imageL = Levetiracetam.svg| widthL = 125| imageR = Levetiracetam ball-and-stick model.png| widthR = 120
lvtˈæᵻæ|m}}| tradename = Keppra, Elepsia, othermonograph|levetiracetam}}| MedlinePlus = a699059| pregnancy_AU = B3| pregnancy_US = C| pregnancy_category = | licence_EU = yes| legal_AU = S4| legal_CA = | legal_UK = | legal_US = Rx-only| licence_US = Levetiracetam| legal_status = Rx-only| routes_of_administration = By mouth, intravenous| class = Racetam anticonvulsant| bioavailability = ~100%| protein_bound = | chemical_formula = H=14 O=2 | molecular_weight = 170.209 g/mol| smiles = O=C1N([C@H](C(=O)N)CC)CCC1correct|chemspider}}| StdInChI = 1S/C8H14N2O2/c1-2-6(8(9)12)10-5-3-4-7(10)11/h6H,2-5H2,1H3,(H2,9,12)/t6-/m0/s1correct|chemspider}}| StdInChIKey = HPHUVLMMVZITSG-LURJTMIESA-N}}Levetiracetam, marketed under the trade name Keppra among others, is a medication used to treat epilepsy. It is used for partial onset, myoclonic, or tonic-clonic seizures. It is taken by mouth as an immediate or extended release formulation or by injection into a vein.Common side effects include sleepiness, dizziness, feeling tired, and aggression.WEB, Levetiracetam Monograph for Professionals,weblink Drugs.com, AHFS, 14 January 2019, en, Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens-Johnson syndrome and anaphylaxis. It is unclear if use is safe during pregnancy but it appears okay when breastfeeding.WEB, Levetiracetam Use During Pregnancy,weblink Drugs.com, 5 March 2019, en, It is the S-enantiomer of etiracetam.BOOK, Cavanna, Andrea E., Behavioural Neurology of Anti-Epileptic Drugs: A Practical Guide, 2018, Oxford University Press, 9780198791577, 17,weblink en, How it works is not clear.Levetiracetam was approved for medical use in the United States in 1999. It is available as a generic medication.BOOK, British national formulary: BNF 76, 2018, Pharmaceutical Press, 9780857113382, 319, 76, A month supply in the United Kingdom costs the NHS about £19.31 per month as of 2019. In the United States the wholesale cost of this amount is about {{USD}}4.50.WEB, NADAC as of 2019-02-27,weblink Centers for Medicare and Medicaid Services, 3 March 2019, en, In 2016 it was the 89th most prescribed medication in the United States with more than 8 million prescriptions.WEB, The Top 300 of 2019,weblink clincalc.com, 22 December 2018,

Medical uses

Focal epilepsy

Levetiracetam is effective as single-drug treatment for newly-diagnosed focal epilepsy in adults.JOURNAL, Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, Trinka E, Brigo F, Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis, Acta Neurol. Scand., 139, 1, 33–41, January 2019, 30194755, 10.1111/ane.13025, It reduces focal seizures by 50% or more as an add-on medication.

Partial-complex epilepsy

Levetiracetam is effective as add-on treatment for partial (focal) epilepsy.JOURNAL, Slater J, Chung S, Huynh L, Duh MS, Gorin B, McMicken C, Ziemann A, Isojarvi J, Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials, Epilepsy Res., 143, 120–129, July 2018, 29784458, 10.1016/j.eplepsyres.2017.10.004,

Generalized epilepsy

Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy.JOURNAL, Nevitt SJ, Sudell M, Weston J, Tudur Smith C, Marson AG, Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data, Cochrane Database Syst Rev, 12, CD011412, December 2017, 29243813, 10.1002/14651858.CD011412.pub3, 6486134, It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures. 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.BOOK, BNF 59, 2010, BMA & RPSGB, Levetiracetam is sometimes used off-label to treat status epilepticusJOURNAL, 10.1007/s12028-012-9695-z, 22528274, Guidelines for the Evaluation and Management of Status Epilepticus, Neurocritical Care, 17, 1, 3–23, 2012, Brophy, Gretchen M., Bell, Rodney, Claassen, Jan, Alldredge, Brian, Bleck, Thomas P., Glauser, Tracy, Laroche, Suzette M., Riviello, James J., Shutter, Lori, Sperling, Michael R., Treiman, David M., Vespa, Paul M., Neurocritical Care Society Status Epilepticus Guideline Writing Committee, JOURNAL, 10.1111/j.1468-1331.2009.02917.x, 20050893, EFNS guideline on the management of status epilepticus in adults, European Journal of Neurology, 17, 3, 348–55, 2010, Meierkord, H., Boon, P., Engelsen, B., Göcke, K., Shorvon, S., Tinuper, P., Holtkamp, M.,

Prevention of seizures

Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury.JOURNAL, Khan NR, VanLandingham MA, Fierst TM, Hymel C, Hoes K, Evans LT, Mayer R, Barker F, Klimo P, Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis, Neurosurgery, 79, 6, 775–782, December 2016, 27749510, 10.1227/NEU.0000000000001445, It may be effective for prevention of seizures associated with subarachnoid hemorrhages.JOURNAL, 10.1016/j.seizure.2009.09.003, 19864168, Utility of levetiracetam in patients with subarachnoid hemorrhage, Seizure, 18, 10, 676–9, 2009, Shah, Dharmen, Husain, Aatif M.,

Other

Levetiracetam has not been found to be useful for treatment of neuropathic pain,JOURNAL, 26132123,weblink 2015, Crawford-Faucher, A, The Role of Levetiracetam in Treating Chronic Neuropathic Pain Symptoms, American Family Physician, 92, 1, 23–4, Huijon, R. M., nor for treatment of essential tremors.JOURNAL, 10.1212/WNL.0b013e318236f0fd, 22013182, 3208950, Evidence-based guideline update: Treatment of essential tremor: Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology, 77, 19, 1752–5, 2011, Zesiewicz, T. A., Elble, R. J., Louis, E. D., Gronseth, G. S., Ondo, W. G., Dewey, R. B., Okun, M. S., Sullivan, K. L., Weiner, W. J., Levetiracetam has not been found to be useful for treating autism,JOURNAL, 10.1016/j.jaac.2013.10.013, 24472258, Practice Parameter for the Assessment and Treatment of Children and Adolescents with Autism Spectrum Disorder, Journal of the American Academy of Child & Adolescent Psychiatry, 53, 2, 237–57, 2014, Volkmar, Fred, Siegel, Matthew, Woodbury-Smith, Marc, King, Bryan, McCracken, James, State, Matthew, JOURNAL, 10.1007/s10803-013-1952-2, 24077782, Antiepileptic Medications in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis, Journal of Autism and Developmental Disorders, 44, 4, 948–57, 2013, Hirota, Tomoya, Veenstra-Vanderweele, Jeremy, Hollander, Eric, Kishi, Taro, but is an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.JOURNAL, 10.3389/fpubh.2013.00031, 24350200, 3859980, A review of traditional and novel treatments for seizures in autism spectrum disorder: Findings from a systematic review and expert panel, Frontiers in Public Health, 1, 31, 2013, Frye, Richard, Rossignol, Daniel, Casanova, Manuel F., Brown, Gregory L., Martin, Victoria, Edelson, Stephen, Coben, Robert, Lewine, Jeffrey, Slattery, John C.,

Special groups

Levetiracetam is a pregnancy category C drug. Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.[14]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 central nervous system (CNS) disorders.[16]Levetiracetam may be safely used with caution in children over the age of 4. However, it has not been determined whether it can be safely given to children under the age of 4.WEB,weblink Advancements in the Treatment of Epilepsy, 1 January 2008, harvard.edu, 8 July 2017,

Adverse effects

The most common adverse effects of levetiracetam treatment include CNS effects 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.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 occurred mostly within the first month of therapy, but they could develop at any time during treatment.JOURNAL, 10.2147/NDT.S1655, 18728811, 2515905, Monotherapy for partial epilepsy: Focus on levetiracetam, Neuropsychiatric Disease and Treatment, 4, 1, 33–8, 2008, Gambardella, Antonio, 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.JOURNAL, 10.1016/j.seizure.2012.09.005, 23036769, Stevens–Johnson syndrome induced by levetiracetam, Seizure, 21, 10, 823–5, 2012, Zou, Li-Ping, Ding, Chang-Hong, Song, Zhen-Jiang, Li, Xiao-Feng, The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.JOURNAL, 10.1111/j.1528-1157.1998.tb01680.x, 9798757, Acute Management of Hypersensitivity Reactions and Seizures, Epilepsia, 39, S17–21, 1998, Griebel, May L., 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.WEB,weblink Keppra (levetiracetam) Prescribing Information, In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than those for other epileptic medications.JOURNAL, 10.1016/j.seizure.2012.04.002, 22541979, Bone mineral density in adult patients treated with various antiepileptic drugs, Seizure, 21, 6, 471–2, 2012, Beniczky, Simona Alexandra, Viken, Janina, Jensen, Lars Thorbjørn, Andersen, Noémi Becser,

Suicide

Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicidal behavior or thoughts. People taking levetiracetam should be monitored closely for signs of worsening depression, suicidal thoughts or tendencies, or any altered emotional or behavioral states.WEB, DailyMed - KEPPRA- levetiracetam tablet,weblink dailymed.nlm.nih.gov, 2015-11-04,

Kidney and liver

Kidney impairment decreases the rate of elimination of levetiracetam from the body. Individuals with reduced kidney function may require dose adjustments. Kidney function can be estimated from the rate of creatinine clearance.Dose adjustment of levetiracetam is not necessary in liver impairment.

Drug interactions

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.JOURNAL, 10.1002/j.1552-4604.2000.tb05984.x, 10868309, Absence of Pharmacokinetic Drug Interaction of Levetiracetam with Phenytoin in Patients with Epilepsy Determined by New Technique, The Journal of Clinical Pharmacology, 40, 6, 590–5, 2000, Browne, T. R., Szabo, G. K., Leppik, I. E., Josephs, E., Paz, J., Baltes, E., Jensen, C. M., The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.JOURNAL, 10.1016/j.eplepsyres.2005.01.005, 15823510, Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: A pooled analysis of data from randomized clinical trials, Epilepsy Research, 64, 1–2, 1–11, 2005, Gidal, Barry E., Baltès, Eugène, Otoul, Christian, Perucca, Emilio,

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 inhbit voltage-dependent Na+ channels, does not affect GABAergic transmission, and does not bind to GABAergic or glutamatergic receptors.JOURNAL, Deshpande LS, Delorenzo RJ, Mechanisms of levetiracetam in the control of status epilepticus and epilepsy, Front Neurol, 5, 11, 2014, 24550884, 3907711, 10.3389/fneur.2014.00011, However, the drug binds to SV2A,JOURNAL, Lynch BA, Lambeng N, Nocka K, etal, The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam, Proc Natl Acad Sci USA, 101, 26, 9861–6, June 2004, 15210974, 470764, 10.1073/pnas.0308208101, 2004PNAS..101.9861L, a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels,JOURNAL, Vogl C, Mochida S, Wolff C, etal, The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca2+ Channels through an Intracellular Pathway, Mol. Pharmacol., 82, 2, 199–208, August 2012, 10.1124/mol.111.076687, 22554805, reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.JOURNAL, Rogawski, MA, Diverse mechanisms of antiepileptic drugs in the development pipeline, Epilepsy Research, 69, 3, 273–94, June 2006, 16621450, 1562526, 10.1016/j.eplepsyres.2006.02.004,

Pharmacokinetics

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.

Distribution

The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).

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.

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.

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.WEB,weblink Levetiracetam Injection Prescribing Information, The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011.WEB, Patent Terms Extended Under 35 USC §156,weblink www.uspto.gov, 2015-11-05, Branch Website Management, JOURNAL, 10.1002/14651858.cd001901.pub2, 22972056, Levetiracetam add-on for drug-resistant focal epilepsy: An updated Cochrane Review, Cochrane Database of Systematic Reviews, 9, CD001901, 2012, Mbizvo, Gashirai K, Dixon, Pete, Hutton, Jane L, Jane Hutton, Marson, Anthony G, The patent for the extended release tablet will expire in 2028.WEB,weblink FDA Access Data, September 12, 2011, November 4, 2015, ANDA 091291, Department of Health and Human Services, Webber, Keith, The branded version Keppra is manufactured by UCB Pharmaceuticals Inc.WEB, Products {{!, UCB |url=http://www.ucb-usa.com/about-ucb/Products |website=www.ucb-usa.com |accessdate=2015-11-05}}In 2015 Aprecia’s 3d-printed orally disintegrating tablet form of the drug was approved by the FDA, under the trade name Spritam.WEB, FDA approves the first 3D-printed drug product {{!, KurzweilAI |url=http://www.kurzweilai.net/fda-approves-the-first-3d-printed-drug-product |website=www.kurzweilai.net |accessdate=2015-10-14 |date=October 13, 2015}}

Research

Levetiracetam is being looked at in psychiatric and neurologic conditions such as Tourette syndrome,JOURNAL, 20628631, 2898169, 2010, Martínez-Granero, M. A., Levetiracetam as an alternative therapy for Tourette syndrome, Neuropsychiatric Disease and Treatment, 6, 309–16, García-Pérez, A, Montañes, F, and anxiety disorder.JOURNAL, Farooq MU, Bhatt A, Majid A, Gupta R, Khasnis A, Kassab MY, Levetiracetam for managing neurologic and psychiatric disorders, Am J Health Syst Pharm, 66, 6, 541–61, 2009, 19265183, 10.2146/ajhp070607, However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.

References

{{reflist}}

External links

{{Racetams}}{{Anticonvulsants}}


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