Levetiracetam

Levetiracetam, marketed under the trade name Keppra among others, is a medication used to treat epilepsy.[1] It is used for partial onset, myoclonic, or tonic-clonic seizures.[1] It is taken by mouth as an immediate or extended release formulation or by injection into a vein.[1]

Levetiracetam
Clinical data
Pronunciation/lɛvɪtɪˈræsɪtæm/
Trade namesKeppra, Elepsia, other
AHFS/Drugs.comMonograph
MedlinePlusa699059
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration
    By mouth, intravenous
    Drug classRacetam anticonvulsant
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability~100%
    Protein binding<10%
    MetabolismEnzymatic hydrolysis of acetamide group
    Elimination half-life6–8 hrs
    ExcretionUrinary
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.121.571
    Chemical and physical data
    FormulaC8H14N2O2
    Molar mass170.209 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Common side effects include sleepiness, dizziness, feeling tired, and aggression.[1] Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens-Johnson syndrome and anaphylaxis.[1] It is unclear if use is safe during pregnancy but it appears okay when breastfeeding.[2] It is the S-enantiomer of etiracetam.[3] How it works is not clear.[1]

    Levetiracetam was approved for medical use in the United States in 1999.[1] It is available as a generic medication.[4] A month supply in the United Kingdom costs the NHS about £19.31 per month as of 2019.[4] In the United States the wholesale cost of this amount is about US$4.50.[5] In 2016, it was the 89th most prescribed medication in the United States with more than eight million prescriptions.[6]

    Medical uses

    Focal epilepsy

    Levetiracetam is effective as single-drug treatment for newly-diagnosed focal epilepsy in adults.[7] It reduces focal seizures by 50% or more as an add-on medication.[8]

    Partial-complex epilepsy

    Levetiracetam is effective as add-on treatment for partial (focal) epilepsy.[9]

    Generalized epilepsy

    Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy.[10] It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures.[11] 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.[12]

    Levetiracetam is sometimes used off-label to treat status epilepticus[13][14]

    Prevention of seizures

    Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury.[15] It may be effective for prevention of seizures associated with subarachnoid hemorrhages.[16]

    Other

    Levetiracetam has not been found to be useful for treatment of neuropathic pain,[17] nor for treatment of essential tremors.[18] Levetiracetam has not been found to be useful for treating autism,[19][20] but is an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.[21]

    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.[22]

    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.[23]

    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.[24]

    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.[25] The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.[26]

    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.[23]

    In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than those for other epileptic medications.[27]

    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.[11]

    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.[23]

    Dose adjustment of levetiracetam is not necessary in liver impairment.[23]

    Drug interactions

    No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.[28] The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.[29]

    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.[30] However, the drug binds to SV2A,[31] a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels,[32] reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.[33]

    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.[23]

    Distribution

    The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).[23]

    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.[23]

    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.[23]

    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.[23][34]

    The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011.[35][8] The patent for the extended release tablet will expire in 2028.[36]

    The branded version Keppra is manufactured by UCB Pharmaceuticals Inc.[37]

    In 2015 Aprecia's 3d-printed orally disintegrating tablet form of the drug was approved by the FDA, under the trade name Spritam.[38]

    Research

    Levetiracetam is being looked at in psychiatric and neurologic conditions such as Tourette syndrome,[39] and anxiety disorder.[40] However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.[40]

    References

    1. "Levetiracetam Monograph for Professionals". Drugs.com. AHFS. Retrieved 14 January 2019.
    2. "Levetiracetam Use During Pregnancy". Drugs.com. Retrieved 5 March 2019.
    3. Cavanna, Andrea E. (2018). Behavioural Neurology of Anti-Epileptic Drugs: A Practical Guide. Oxford University Press. p. 17. ISBN 9780198791577.
    4. British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 319. ISBN 9780857113382.
    5. "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
    6. "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
    7. Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, Trinka E, Brigo F (January 2019). "Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis". Acta Neurol. Scand. 139 (1): 33–41. doi:10.1111/ane.13025. PMID 30194755.
    8. Mbizvo, Gashirai K; Dixon, Pete; Hutton, Jane L; Marson, Anthony G (2012). "Levetiracetam add-on for drug-resistant focal epilepsy: An updated Cochrane Review". Cochrane Database of Systematic Reviews (9): CD001901. doi:10.1002/14651858.cd001901.pub2. PMID 22972056.
    9. Slater J, Chung S, Huynh L, Duh MS, Gorin B, McMicken C, Ziemann A, Isojarvi J (July 2018). "Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials". Epilepsy Res. 143: 120–129. doi:10.1016/j.eplepsyres.2017.10.004. PMID 29784458.
    10. Nevitt SJ, Sudell M, Weston J, Tudur Smith C, Marson AG (December 2017). "Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data". Cochrane Database Syst Rev. 12: CD011412. doi:10.1002/14651858.CD011412.pub3. PMC 6486134. PMID 29243813.
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    12. BNF 59. BMA & RPSGB. 2010.
    13. 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 (2012). "Guidelines for the Evaluation and Management of Status Epilepticus". Neurocritical Care. 17 (1): 3–23. doi:10.1007/s12028-012-9695-z. PMID 22528274.
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    21. Frye, Richard; Rossignol, Daniel; Casanova, Manuel F.; Brown, Gregory L.; Martin, Victoria; Edelson, Stephen; Coben, Robert; Lewine, Jeffrey; Slattery, John C. (2013). "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. doi:10.3389/fpubh.2013.00031. PMC 3859980. PMID 24350200.
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    25. Zou, Li-Ping; Ding, Chang-Hong; Song, Zhen-Jiang; Li, Xiao-Feng (2012). "Stevens–Johnson syndrome induced by levetiracetam". Seizure. 21 (10): 823–5. doi:10.1016/j.seizure.2012.09.005. PMID 23036769.
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    28. Browne, T. R.; Szabo, G. K.; Leppik, I. E.; Josephs, E.; Paz, J.; Baltes, E.; Jensen, C. M. (2000). "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. doi:10.1002/j.1552-4604.2000.tb05984.x. PMID 10868309.
    29. Gidal, Barry E.; Baltès, Eugène; Otoul, Christian; Perucca, Emilio (2005). "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. doi:10.1016/j.eplepsyres.2005.01.005. PMID 15823510.
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    40. Farooq MU, Bhatt A, Majid A, Gupta R, Khasnis A, Kassab MY (2009). "Levetiracetam for managing neurologic and psychiatric disorders". Am J Health Syst Pharm. 66 (6): 541–61. doi:10.2146/ajhp070607. PMID 19265183.CS1 maint: uses authors parameter (link)
    • "Levetiracetam". Drug Information Portal. U.S. National Library of Medicine.
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