Oxcarbazepine

Oxcarbazepine

File:Orcarbazepine 3d structure.png
Systematic (IUPAC) name
10,11-dihydro- 10-oxo- 5H-dibenz(b,f)azepine- 5-carboxamide
Clinical data
Pronunciation	/ɒks.kɑːrˈbæz.ᵻˌpiːn/
Trade names	Trileptal
AHFS/Drugs.com	monograph
MedlinePlus	a601245
Pregnancy category	US: C (Risk not ruled out)
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral (Tablets or Suspension)
Pharmacokinetic data
Bioavailability	> 95%
Protein binding	?
Metabolism	Hepatic (Cytosolic Enzymes & Glucuronic Acid)
Biological half-life	1–5 hours (healthy adults)
Excretion	Renal (<1%)
Identifiers
CAS Number	28721-07-5 Y
ATC code	N03AF02 (WHO)
PubChem	CID: 34312
IUPHAR/BPS	7254
DrugBank	DB00776 Y
ChemSpider	31608 Y
UNII	VZI5B1W380 Y
KEGG	D00533 Y
ChEMBL	CHEMBL1068 Y
Chemical data
Formula	C15H12N2O2
Molecular mass	252.268 g/mol
SMILES O=C3c1c(cccc1)N(c2ccccc2C3)C(=O)N
InChI 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) Y Key:CTRLABGOLIVAIY-UHFFFAOYSA-N Y
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Oxcarbazepine is an anticonvulsant drug primarily used in the treatment of epilepsy. There is some evidence for oxcarbazepine as a mood-stabilizing agent 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.

Common side effects include nausea, vomiting, dizziness, drowsiness, headache, double vision and trouble with walking. Although not common, anaphylaxis may occur. Due to its structural similarities to carbamazepine there is approximately a 25-30% chance of cross-reactivity between the two medications.

Oxcarbazepine is marketed as Trileptal by Novartis and available in some countries as a generic drug. There is also an extended-release formation marketed as Oxtellar XR by Supernus Pharmaceuticals.

Medical uses

Oxcarbazepine is an anticonvulsant used to reduce the occurrence of epileptic episodes, and is not intended to cure epilepsy. Oxcarbazepine is used alone or in combination with other medications for the treatment of focal (partial) seizures in adults. In pediatric populations, it can be used by itself for the treatment of partial seizures for children 4 years and older, or in combination with other medications for children 2 years and older.

In addition, oxcarbazepine has been shown to improve mood and reduce anxiety; therefore, it is a potential option for add-on therapy in the treatment of bipolar disorder.

Pregnancy

Oxcarbazepine is listed as Pregnancy Category C.

Currently, there is limited data analyzing the impact of oxcarbazepine on a human fetus. Animal studies have shown an increased incidence of fetal abnormalities in pregnant rats and rabbits treated with oxcarbazepine, during pregnancy. In addition, oxcarbazepine is structurally similar to carbamazepine (pregnancy category: D) which is considered to be teratogenic in humans. Oxcarbazepine should only be used in pregnancy if the benefits justify the risks.

Pregnant persons on oxcarbazepine should be closely monitored, as plasma levels of the active metabolite (MHD) has been shown to potentially decrease during pregnancy.

Nursing mothers

Oxcarbazepine and MHD are both present in human breast milk and thus, some of the active drug can be transferred to a nursing infant. When considering whether to continue this medication in nursing mothers, the impact of the drug's side effect profile on the infant, should be weighed against its anti-epileptic benefit for the mother.

Side effects

The most common side effects associated with oxcarbazepine include:

• dizziness (6.4%)
• blurred or double vision (2.1%)
• fatigue (2.1%)
• headaches (2.9%)
• nausea (4.9%)
• vomiting (2%)
• sleepiness (2.4%)
• There is evidence of difficulty in concentration and mental sluggishness.

Other rare side effects of oxcarbazepine include:

• severe low blood sodium (1%)
• anaphylaxis / angioedema
• hypersensitivity (especially if experienced with carbamazepine previously [25-30% cross-reactivity])
• Toxic epidermal necrolysis (TEN, 0.5 to 6 cases per million-person years)
• Stevens–Johnson syndrome (SJS, 0.5 to 6 cases per million-person years)
• Thoughts of suicide (<1%)

Serum sodium levels should be considered in maintenance treatment or symptoms of hyponatremia develop. 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 people could experience severe sunburns as a result of sun exposure.

Interactions

Oxcarbazepine and its active metabolite (MHD) have been shown to exhibit drug interactions when indicated with medications that are metabolized via CYP 450. Oxcarbazepine and MHD is a potent inhibitor of CYP2C19 and thus, has the potential to increase plasma concentration of drugs that are metabolized through this pathway placing the patient at higher risk for toxicities. Example of CYP2C19 substrates include: phenytoin, citalopram, diazepam, imipramine, omeprazole, propranolol, amitriptyline and progesterone when administered together.

In addition, oxcarbazepine and MHD are CYP3A4 & CYP3A5 inducers and thus, have the potential to decrease the plasma concentration and therapeutic efficacy of medications that are CYP3A substrates. Examples of CYP3A4 substrates include dihydropyridine calcium channel antagonist and oral contraceptives. Due to the increase in drug metabolism of CYP3A4 substrates, hormonal contraceptives might be less effective, placing females at a greater risk of pregnancy.

Furthermore, oxcarbazepine has been shown to interact with other anticonvulsant medications when used in combination. For example, phenytoin and phenobarbital are known CYP inducers and thus, have the potential to decrease the plasma concentration of oxcarbazepine's active metabolite, MHD.

Pharmacokinetics

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

Pharmacodynamics

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

Pharmacology

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. Furthermore, anticonvulsant effects of these compounds could be attributed to enhanced potassium conductance and modulation of high-voltage activated calcium channels.

Pharmacogenetics

Trileptal (oxcarbazepine), oral suspension 100 mg/ml

Since the structure of oxcarbazepine is similar to carbamazepine, there is a consideration for genetic testing in patients who are of Asian descent (mainly populations of Han Chinese (2-12%), Thai (8%), Philippines (15%), Malaysia) due to the higher frequency of the HLA-B*1502 allele. Human leukocyte antigen (HLA) allele B*1502 has been associated with an increased incidence of Stevens–Johnson syndrome and toxic epidermal necrolysis.

Structure pharmacology

Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon–carbon double bond on the dibenzazepine ring at the 10 position (10-keto). This difference helps reduce the impact on the liver of metabolizing the drug, and also prevents the serious forms of anemia or agranulocytosis occasionally associated with carbamazepine. Aside from this reduction in side effects, it is thought to have the same mechanism as carbamazepine – sodium channel inhibition (presumed to be the main mechanism of action) – and is generally used to treat the same conditions.

Oxcarbazepine is a prodrug which is activated to eslicarbazepine in the liver.

History

File:Trileptal tablets.jpg

300mg Trileptal tablets

First made in 1965, 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 pleaded guilty to marketing Trileptal for the unapproved uses of neuropathic pain and bipolar disorder.

See also

• Carbamazepine
• Eslicarbazepine acetate
• Lamotrigine

External links

• RxList entry
• DrugBank entry