Gabewong group14/sandbox
Clinical data
Trade namesTrileptal
AHFS/Drugs.comMonograph
MedlinePlusa601245
Routes of
administration
Oral (Tablets or Suspension) [1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability> 95%
Protein binding?
MetabolismHepatic
(Cytosolic Enzymes & Glucuronic Acid)
Elimination half-life1–5 hours (healthy adults)
ExcretionRenal (<1%)[1]
Identifiers
  • 10,11-dihydro- 10-oxo- 5H-dibenz(b,f)azepine- 5-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC15H12N2O2
Molar mass252.268 g/mol g·mol−1
3D model (JSmol)
  • O=C3c1c(cccc1)N(c2ccccc2C3)C(=O)N
  • InChI=1S/C15H12N2O2/c16-15(19)17-12-7-3-1-5-10(12)9-14(18)11-6-2-4-8-13(11)17/h1-8H,9H2,(H2,16,19) checkY
  • Key:CTRLABGOLIVAIY-UHFFFAOYSA-N checkY
  (verify)

Oxcarbazepine /ɒks.kɑːrˈbæz.[invalid input: 'ɨ']ˌpn/ is an anticonvulsant primarily used in the treatment of epilepsy. [1] There is some evidence for oxcarbazepine as a mood-stabilizing drug and thus it can be used as add-on therapy for bipolar disorder, in patients that have failed or are unable to tolerate approved treatments. [2] Oxcarbazepine is structurally similar to carbamazepine with an observed 25-30% chance of cross-reactivity between the two medications. [1] Oxcarbazepine is marketed as Trileptal by Novartis and available in some countries as a generic drug.

Medical uses

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Oxcarbazepine is FDA approved as a monotherapy or adjunct therapy in the treatment of Focal (partial) seizures in adults. It is used as monotherapy for partial seizures in children 4 years and older. In children above 2 years, it is used as an adjunct treatment for partial seizures.[1] In treatment of epilepsy, oxcarbazepine has recently been found to be associated with a greater enhancement in mood and reduction in anxiety symptoms than other drugs employed to treat epilepsy.[2] The usage of this drug does not cure a person of epilepsy but will help prevent seizure episodes.[3]

It also appears to be effective in approximately half of patients with bipolar disorder and is well tolerated.[4]

Pharmacokinetics

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Oxcarbazepine has great bioavailability once it is administrated orally as tablets[5]. Upon absorption, oxcarbazepine is largely metabolized to its pharmacologic active 10- monohydroxy metabolite (MHD)[5]. During a study in humans, the unchanged oxcarbazepine was found to be about 2% of the total radioactivity, while MHD presented 70%, and the rest representing the minor metabolites[5]. The half-life of oxcarbazepine is considered to be about 2 hours, whereas the active metabolite (MHD) has a half-life of nine hours. Therefore, the antiepileptic activity can be attributed to MHD.[5]

Pharmacodynamics

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Both oxcarbazepine and its MHD the active metabolite were found to show anticonvulsant properties in seizure models done on animals[5]. These compounds had protective functions whenever tonic extension seizures were induced electrically[5]. Such protection was less apparent whenever seizures were induced chemically.[5] There was no observable tolerance during a 4 weeks course of treatment with daily administration of oxacarbazepine or MHD in electroshock test on mice and rats[5].

Pharmacology

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Oxcarbazepine and MHD exert their action by blocking voltage-sensitive sodium channels, thus leading to the stabilization of hyper excited neural membranes, suppression of repetitive neuronal firing and diminishment propagation of synaptic impulses[6]. Furthermore, anticonvulsant effects of these compounds could be attributed to enhanced potassium conductance and modulation of hig-voltage activated calcium channels[6].

Pharmacogenetics

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Since the structure of oxcarbazepine is similar to carbamazepine, there is a consideration for genetic testing in patients who are of Asian decent (mainly populations of Han Chinese (2-12%), Thai (8%), Philippines (15%), Malaysia) due to the higher frequency of the HLA-B*1502 Allele[1]. Human Leukocyte Antigen (HLA) allele B*1502 has been associated with an increased incidence of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis[1].

Side effects

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The most common side effects associated with Oxcarbazepine include[1]:

  • dizziness
  • drowsiness
  • blurred or double vision
  • fatigue
  • headaches
  • nausea
  • vomiting
  • sleepiness
  • There is evidence of difficulty in concentration and mental sluggishness.

Other rare side effects of Oxcarbazepine include[1]:

Serum sodium levels should be considered in maintenance treatment or symptoms of hyponatremia develop.[1] Some side effects (such as headache) are more pronounced shortly after a dose is taken and tend to fade with the passage of time (60 to 90 minutes). Other side effects include stomach pain, tremor, rash, diarrhea, constipation, decreased appetite and dry mouth. Photosensitivity is a potential side-effect and patients could experience severe sunburns as a result of sun exposure.[1] The frequency of adverse effects rises above a daily dosage of 1200 mg. Some patients reported a sensation of incontinence without cause after taking the drug.

Contraindications

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This medication is to be avoided in any person with known hypersensitivity to oxcarbazepine[6].

Interactions

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When assessed in human liver microsomes, oxcarbazepine and its active metabolite (MHD) were found to inhibit CYP2C19[6].Consequently, administrating drugs that are also metabolized by this enzyme (phenobarbitone, phenytoin, citalopram, diazepam, hexobarbitone, imipramine, omeprazole, proguanil, propranolol, lansoprazole, amitriptyline, clomipramine, cyclophosphamide and progesterone) with significant doses of oxcarbazepine could have important clinical implications[6].Oxcarbazepine and MHD were also responsible of inducing the cytochromes CYP3A4 and CYP3A5 in vitro and in vivo studies[6]. These enzymes are known to metabolize drugs such as dihydropyridine calcium antagonists, oral contraceptives, and antiepilectic drugs, causing a smaller plasma concentration of these drugs[6].

Special Population

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Pregnancy

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Oxcarbazepine is listed as Pregnancy Category C. [1]

Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals (rats and rabbits) treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose.

There are no adequate and well-controlled clinical studies of oxcarbazepine in pregnant women; however, oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic (causing developmental abnormalities) in humans. Given this fact, and the results of the animal studies described, it is likely that oxcarbazepine is a human teratogen. Oxcarbazepine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy patients on oxcarbazepine should be closely monitored, since plasma levels of the active metabolite (MHD) has been shown to potentially decrease during pregnancy. [1]

Oxcarbazepine may cause oral hormonal contraceptives to be less effective.[7]

Nursing mothers

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Oxcarbazepine and its active metabolite MHD are excreted in human breast milk. Because of the potential for serious adverse reactions to oxcarbazepine in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women.

History

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First synthesized in 1965,[citation needed] it was patent-protected by Geigy in 1969 through DE 2011087 . It was approved for use as an anticonvulsant in Denmark in 1990, Spain in 1993, Portugal in 1997, and eventually for all other EU countries in 1999. It was approved in the US in 2000. In September 2010, Novartis pled guilty to marketing Trileptal for the unapproved uses of neuropathic pain and bipolar disorder during 2000 and 2001.[8]

 
300mg Trileptal tablets

See also

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References

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  1. ^ a b c d e f g h i j k l m "Oxcarbazepine Drug Label".
  2. ^ a b Mazza M, Nicola M, Martinotti G, Taranto C, Pozzi G, Conte G, Janiri L, Bria P, Mazza S (April 2007). "Oxcarbazepine in bipolar disorder: a critical review of the literature". Expert Opinion on Pharmacology. 8 (5): 649–656. doi:10.1517/14656566.8.5.649. PMID 17376019. S2CID 25068107. Cite error: The named reference "Mazza_2007" was defined multiple times with different content (see the help page).
  3. ^ Information, National Center for Biotechnology; Pike, U. S. National Library of Medicine 8600 Rockville; MD, Bethesda; Usa, 20894. "Oxcarbazepine (By mouth) - National Library of Medicine - PubMed Health". mmdn/DNX1023. Retrieved 2015-11-02. {{cite web}}: |first4= has numeric name (help)CS1 maint: numeric names: authors list (link)
  4. ^ Ghaemi SN, Berv DA, Klugman J, Rosenquist KJ, Hsu DJ (August 2003). "Oxcarbazepine treatment of bipolar disorder". J Clin Psychiatry. 64 (8): 943–5. doi:10.4088/JCP.v64n0813. PMID 12927010.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b c d e f g h "DailyMed - OXCARBAZEPINE- oxcarbazepine suspension". dailymed.nlm.nih.gov. Retrieved 2015-11-02.
  6. ^ a b c d e f g "Trileptal (oxarbazepine)" (PDF).
  7. ^ Reimers, A (September 2014). "New antiepileptic drugs and women". Seizure. 23 (8): 585–591. doi:10.1016/j.seizure.2014.05.004. PMID 24908139. S2CID 18290893.
  8. ^ U.S. District Court for the Eastern District of Pennsylvania. "Government's memorandum for entry of plea and sentencing" (PDF).
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Category:Anticonvulsants Category:Mood stabilizers Category:Ureas Category:Dibenzazepines Category:Ketones Category:Teratogens Category:Embryotoxicants