Oxcarbazepine

154.8 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID0045703]

152.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

153.8 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

148.8 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Oxcarbazepine may induce metabolism of some calcium-channel blocking agents (e.g., felodipine, verapamil), possibly via induction of CYP3A4 and CYP3A5 isoenzymes, resulting in decreased AUC of the calcium-channel blocking agents.

Oxcarbazepine may induce metabolism of oral estrogen-progestin contraceptives, possibly via induction of CYP3A4 and CYP3A5, resulting in decreased area under the plasma concentration-time curve (AUC) and consequent decreased efficacy of the contraceptives.

Oxcarbazepine may inhibit metabolism of other anticonvulsants (e.g., phenobarbital, phenytoin), possibly via inhibition of the cytochrome P-450 (CYP) isoenzyme 2C19, resulting in increased plasma concentrations of these drugs. Oxcarbazepine dosages exceeding 1200 mg daily may increase plasma phenytoin concentrations by 40% and, therefore, when such dosages of oxcarbazepine are used concomitantly with phenytoin, dosage reduction of phenytoin may be required. Potent inducers of CYP isoenzymes (e.g., carbamazepine, phenytoin, phenobarbital) may decrease plasma concentrations of oxcarbazepine and its active 10-monohydroxy metabolite (MHD).

Oxcarbazepine and its 10-monohydroxy metabolite may increase the concentration of phenobarbital by about 14%; at oxcarbazepine doses above 1200 mg a day; phenytoin concentrations may be increased by about 40%.

For more Interactions (Complete) data for OXCARBAZEPINE (6 total), please visit the HSDB record page.

Chronic therapy with oxcarbazepine is associated with elevations in serum aminotransferase levels in a small proportion of patients. These elevations are rarely clinically significant and do not usually require dose modification. Clinically apparent hepatotoxicity from oxcarbazepine is uncommon but described, and is less common than occurs with carbamazepine. Oxcarbazepine hepatotoxicity usually arises in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, followed by rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia 2 to 8 weeks after starting therapy. The liver involvement ranges from a mild and transient elevation in serum enzymes to abrupt onset of an acute hepatitis-like syndrome, that can be severe and even fatal. The typical enzyme elevations are usually mixed, but can be either hepatocellular or cholestatic. Liver biopsy shows mixed necroinflammatory-cholestatic injury with prominence of eosinophils and occasionally granulomas.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 360(SRC), determined from a structure estimation method(2), indicates that oxcarbazepine is expected to have moderate mobility in soil(SRC). Volatilization of oxcarbazepine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.9X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Oxcarbazepine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.6X10-9 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2007).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 360(SRC), determined from a structure estimation method(2), indicates that oxcarbazepine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 6.9X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of <1(SRC), from an estimated log Kow of 1.11(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2007).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), oxcarbazepine, which has an estimated vapor pressure of 7.6X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase oxcarbazepine may be removed from the air by wet or dry deposition(SRC). Oxcarbazepine contains chromophores that absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

Oxcarbazepine can lead to central nervous system (CNS) side effects due to its blockade of voltage-sensitive sodium channels. Some common side effects that patients experience when taking oxcarbazepine are sedation, dizziness, abnormal gait, headache, ataxia, fatigue, confusion, nausea, vomiting, abdominal pain, or rash. Hyponatremia and increased suicidal ideation are among the most dangerous and life-threatening side effects patients may experience while taking oxcarbazepine. Weight gain and sedation can occur as well in a minority of patients. Patients who have experienced hypersensitivity with carbamazepine are more likely to experience hypersensitivity with oxcarbazepine.

Completely absorbed following oral administration. Food has no effect on the rate and extent of absorption of oxcarbazepine. After single-dose administration of Trileptal tablets to healthy male volunteers under fasted conditions, the median tmax was 4.5 (range 3 to 13) hours. After single-dose administration of Trileptal oral suspension to healthy male volunteers under fasted conditions, the median tmax was six hours. Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when Trileptal is given twice a day.

Oxcarbazepine studies conducted in rats and dogs over 3 and 6 months have shown reversible, dose-dependent increases in liver weight, which are attributed to centrilobular megalocytosis. Oxcarbazepine metabolism differs significantly between humans and rats; therefore, this toxicity cannot be generalized to human patients.

The exact mechanism by which oxcarbazepine exerts its anticonvulsant effect is unknown. It is known that the pharmacological activity of oxcarbazepine occurs primarily through its 10-monohydroxy metabolite (MHD). In vitro studies indicate an MHD-induced blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neuronal membranes, inhibition of repetitive neuronal discharges, and diminution of propagation of synaptic impulses.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of oxcarbazepine can be estimated to be 360(SRC). According to a classification scheme(2), this estimated Koc value suggests that oxcarbazepine is expected to have moderate mobility in soil.

/SIGNS AND SYMPTOMS/ Serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in adults and children receiving oxcarbazepine; reactions have been life-threatening, have required hospitalization, and rarely have been fatal. The incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis reported in patients receiving oxcarbazepine exceeds the rate in the general population by threefold to tenfold. The median time to onset of these reactions was 19 days. Recurrence of serious dermatologic reactions following rechallenge with oxcarbazepine has occurred.

/CASE REPORTS/ Hyponatremia is a commonly encountered clinical problem with potentially severe complications. Among the underlying implicated etiologies are medications such as oxcarbazepine, which has been well documented and attributed to the syndrome of inappropriate antidiuretic hormones (SIADH). ... The case of a 28-year-old woman with a diagnosis of secondary antiphospholipid syndrome who presented with asymptomatic hyponatremia secondary to excessive water intake after oxcarbazepine ingestion, suggesting a new mechanism for oxcarbazepine-induced hyponatremia /is reported/.

/CASE REPORTS/ Oxcarbazepine is a analogue of carbamazepine with anticonvulsant and analgesic activity. We report a case of localized penile edema caused by oxcarbazepine. The association between the drug and the adverse reaction was confirmed by rechallenge test. ...

/CASE REPORTS/ A 70-year-old patient treated with oxcarbazepine experienced severe hyponatremia. The patient used oxcarbazepine (600 mg twice a day) concomitantly with diuretics (torasemide 10 mg and indapamide 1.25 mg once per day), perindopril, an angiotensin-converting enzyme inhibitor, and amlodipine, a Ca(2+) channel blocker. The patient complained of a nausea, malaise, diplopia, drowsiness, apathy, decreased diuresis (creatinine clearance - 41.51 ml/min), and exacerbation of epileptic seizures. Sodium concentration in the plasma was 113 mmol/L. The patient was hospitalized. It was suggested that a decrease in plasma sodium concentration was caused by oxcarbazepine used together with diuretics for six months. Oxcarbazepine-induced hyponatremia is reported in 22.2-50% of patients, although symptoms are present only in 5.9% of patients. The most common symptoms of central nervous system injury, experienced by patients, are drowsiness, dizziness, decreased cognitive function, coordination impairment, etc. ...

For more Human Toxicity Excerpts (Complete) data for OXCARBAZEPINE (9 total), please visit the HSDB record page.

The plasma half-life of oxcarbazepine is approximately 2 hours and the plasma half-life of MHD is approximately 9 hours.

Oxcarbazepine: 2 hours. 10-Monohydroxy metabolite: 9 hours. Note: In patients with renal function impairment with a creatinine clearance < 30 mL/minute, the half life of 10 monohydroxy metabolite is prolonged to 10 hours ...

... Elimination half-lives in healthy volunteers are 1-5 hours for oxcarbazepine and 7-20 hours for 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD). Longer and shorter elimination half-lives have been reported in elderly volunteers and children, respectively. ...

Oxcarbazepine is rapidly and extensively metabolized to its primary metabolite, MHD, which is responsible for the bulk of its anti-epileptic activity and exists in much higher concentrations in the plasma than the parent drug. MHD is formed via reduction by several members of the aldo-keto reductase family of cytosolic liver enzymes and exists as a racemate in plasma in an approximate ratio of 80% (S)-MHD to 20% (R)-MHD. MHD is further metabolized to glucuronide conjugate metabolites for excretion, and small amounts are oxidized to 10-,11-dihydro-10,11-dihydroxycarbamazepine (DHD) which is pharmacologically inactive. Only 10% of an administered dose of oxcarbazepine will remain as either the parent drug or glucuronide conjugates of the parent drug.

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.

The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of (14)C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Fecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects. In the 0-6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47,779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary (14)C. Unchanged oxcarbazepine, and its sulfate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47,779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favoring the S-configuration of GP 47,779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.

... The interaction potential of oxcarbazepine is relatively low. However, enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital or carbamazepine can reduce slightly the concentrations of 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD). Verapamil may moderately decrease MHD concentrations, but this effect is probably without clinical relevance. The influence of oxcarbazepine on other antiepileptic drugs is not clinically relevant in most cases. However, oxcarbazepine appears to increase concentrations of phenytoin and to decrease trough concentrations of lamotrigine and topiramate. Oxcarbazepine lowers concentrations of ethinylestradiol and levonorgestrel, and women treated with oxcarbazepine should consider additional contraceptive measures. Due to the absent or lower enzyme-inducing effect of oxcarbazepine, switching from carbamazepine to oxcarbazepine can result in increased serum concentrations of comedication, sometimes associated with adverse effects. ...

Oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD) by cytosolic enzymes. MHD is metabolized further by conjugation with glucuronic acid. Route of Elimination: Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. Fecal excretion accounts for less than 4% of the administered dose. Half Life: The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most anti-epileptic activity.

VZI5B1W380

OXCARBAZEPINE

Established Pharmacologic Class [EPC] - Anti-epileptic Agent

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

Oxcarbazepine is an Anti-epileptic Agent. The physiologic effect of oxcarbazepine is by means of Decreased Central Nervous System Disorganized Electrical Activity.

OXCARBAZEPINE

Drugs used to prevent SEIZURES or reduce their severity.

A class of drugs that inhibit the activation of VOLTAGE-GATED SODIUM CHANNELS.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP3A.

Oxcarbazepine is completely absorbed following oral administration. A single 600mg dose of oxcarbazepine resulted in an MHD Cmax of 34 μmol/L and a median Tmax of 4.5 hours. When administered twice daily, steady-state levels of MHD are attained within 2-3 days. The rate and extent of absorption of oxcarbazepine is not affected by food intake.

Following oral administration, more than 95% of the administered dose of oxcarbazepine is found in the urine. Of this, approximately 49% is MHD glucuronide metabolites, 27% is unchanged MHD, 3% is inactive DHD metabolites, 13% is conjugated oxcarbazepine, and less than 1% is unchanged parent drug. Fecal elimination accounts for only 4% of the administered dose.

The apparent volume of distribution of oxcarbazepine is 49 L. The apparent volumes of distribution of (S)- and (R)-MHD were found to be 23.6 L and 31.7 L, respectively.

Plasma clearance of oxcarbazepine has been estimated to be approximately 84.9 L/h, whereas plasma clearance of its active metabolite, MHD, was estimated to be 2.0 L/h. Rapid metabolic clearance appears to be the main pathway for oxcarbazepine, while clearance of its metabolites occurs mainly via renal excretion.

Oxcarbazepine is completely absorbed. Food does not alter the rate and extent of absorption of oxcarbazepine.

Both oxcarbazepine and its active 10-monohydroxy metabolite (MHD) are distributed into milk in humans.