Oxcarbazepine

Absorption

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.

Toxicity

The oral LD50 of oxcarbazepine in mammals is 1240 mg/kg and the oral TDLo in children has been reported to be 73 mg/kg. Isolated cases of oxcarbazepine overdose have been reported - patients who ingested up to 24,000mg recovered with symptomatic treatment. Symptoms may include respiratory and CNS depression, movement-related disorders (e.g. dyskinesia, ataxia), nausea/vomiting, hyponatremia, or QTc prolongation. There is no antidote for oxcarbazepine overdose - management should consist of supportive and symptomatic treatment, and consideration should be given to the use of gastric lavage or activated charcoal.

Description

Oxcarbazepine is a new antiepileptic carbamazepine derivative, reportedly better tolerated than carbamazepine. It appears to be most effective in partial epilepsy with complex seizures.

Chemical properties

Pale Yellow Powder

Originator

Ciba-Geigy (Switzerland)

The Uses of Oxcarbazepine

Oxcarbazepine is a sodium channel protein inhibitor and a beta-adrenergic blocker. It is an anticonvulsant and mood-stab.The keto derivative of Carbamazepine. Used as an anticonvulsant.

Background

Oxcarbazepine is an anti-epileptic medication used in the treatment of partial onset seizures that was first approved for use in the United States in 2000. It is a structural derivative of carbamazepine and exerts a majority of its activity via a pharmacologically active metabolite, MHD, which exists as a racemate in the blood - a pro-drug of the more active (S)-enantiomer is also marketed as a separate anti-epileptic under the name eslicarbazepine. Compared to other anti-epileptic drugs, which are generally metabolized via the cytochrome P450 system, oxcarbazepine has a reduced propensity for involvement in drug-drug interactions owing to its primarily reductive metabolism.

Indications

In the United States, oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial-onset seizures in adults and as monotherapy in the treatment of partial-onset seizures in pediatric patients aged 4 years and above, and as adjunctive therapy in pediatric patients aged 2 years and above with partial-onset seizures.
In Canada, oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial-onset seizures in patients 6 years of age and older.

Definition

ChEBI: A dibenzoazepine derivative, having a carbamoyl group at the ring nitrogen, substituted with an oxo group at C-4 of the azepeine ring which is also hydrogenated at C-4 and C-5. It is a anticholinergic anticonvulsant and mood stabilizing drug, used primaril in the treatment of epilepsy.

brand name

Trileptal (Novartis).

Biological Functions

Oxcarbazepine is chemically and pharmacologically closely related to carbamazepine, but it has much less capacity to induce drug-metabolizing enzymes. This property decreases the problems associated with drug interactions when oxcarbazepine is used in combination with other drugs. The clinical uses and adverse effect profile of oxcarbazepine appear to be similar to those of carbamazepine.

General Description

Oxcarbazepine, marketed under the trade name Trileptal^?, is an anticonvulsant developed and prescribed for treatment of epilepsy. In recent years, Oxcarbazepine has shown efficacy in treatment of mood disorders. This certified solution standard is suitable as starting material for the preparation of calibrators and controls in oxcarbazepine testing by GC/MS or LC-MS/MS.

Biological Activity

Anticonvulsant; protects mice and rats against generalized tonic-clonic seizures induced by electroshock. Thought to act via inhibition of sodium channel activity.

Biochem/physiol Actions

Anticonvulsant, antineuralgic. Inhibits veratrine-induced transmitter release.

Mechanism of action

Although oxcarbazepine is less potent that CBZ, its mechanism of action is similar. The majority of the pharmacological activity for oxcarbazepine is attributed to its primary metabolite, 10-monohydroxycarbazepine (MHD), the plasma levels of which may be ninefold higher than those for CBZ. Both oxcarbazepine and MHD produce a blockade of voltagedependent sodium channels, thus decreasing repetitive firing and spread of electrical activity. An additional action on calcium and potassium channels may contribute to the therapeutic effect. Like carbamazepine, oxcarbazepine may worsen juvenile myoclonic or absence seizures.

Pharmacokinetics

Oxcarbazepine is completely absorbed, and food does not affect its absorption. Unlike CBZ, it does not cause autoinduction of its metabolism. The metabolism of oxcarbazepine is different from that of CBZ. Oxcarbazepine is reduced by cytosolic enzymes to MHD before its O-glucuronidation. More than 95% of its oral dose is excreted as conjugated metabolites, with approximately 4% of the drug converted to inactive 10,11-dihydroxy CBZ. Unlike CBZ, no epoxide nor aromatic hydroxylation metabolites are formed. The half-life is 2 hours for oxcarbazepine and 9 hours for the active 10-monohydroxy metabolite. In patients with impaired renal function, the half-life for MHD is prolonged to 19 hours, doubling its area under the plasma concentration curve. Peak plasma concentration following an oral dose occurs at approximately 4.5 hours.

Oxcarbazepine induces CYP3A4/5 and UTP, and it also inhibits CYP2C19, producing significant effects on the plasma concentration of other drugs. Therefore, oxcarbazepine decreases felodipine bioavailability and lowers plasma levels for lamotrigine, CBZ, CBZ epoxide, calcium channel blockers, and oral contraceptives. Oxcarbazepine increases plasma levels of phenobarbital and phenytoin. Unlike carbamazepine, oxcarbazepine has no effect on plasma levels of risperidone or olanzepine. The plasma levels for oxcarbazepine or MHD are decreased by CBZ, phenobarbital, phenytoin, valproate, and verapamil. Serum MHD may decrease during pregnancy but increase following delivery. Oxcarbazepine clearance is reduced in renal impairment and the elderly. In children, a higher dose/kg of oxcarbazepine than in adults is required to obtain an effective plasma concentration.

Clinical Use

Oxcarbazepine (Trileptal?) is the 10-keto analogue of carbamazepine. It is indicated as monotherapy or adjunctive therapy for partial seizures in adults with epilepsy, as monotherapy for the treatment of partial seizures in children 4 years of age or older, and as adjunct therapy in children 2 to 4 years of age.

Side Effects

Patients with hypersensitivity reactions to carbamazepine can be expected to show cross-sensitivity (e.g., rash) or related problems to oxcarbazepine. The improved toxicity profile for oxcarbazepine when compared to CBZ may result from absence of the epoxide or CBZ-iminoquinone metabolites. The most common side effects are headache, dizziness, nystagmus, blurred vision, somnolence, nausea, ataxia, and fatigue. The incidence of adverse effects has been related to elevated serum MHD concentrations. Adverse effects on cognitive status, hyponatremia, and serious dermatological reactions have been reported, as has hyponatremia.

Synthesis

Oxcarbazepine can be obtained in two different ways.
1) Reaction of 10-methoxy-5H-dibenz[b,f]azepine (1) with phosgene gives the 5- chlorocarbonyl compound, treatment with NH3 affords 10-methoxy-5H-dibenz[b,f ]azepine-5-carboxamide (2), which is hydrolyzed with diluted HCl to oxcarbazepine.
2) Nitration of 5-cyano-5H-dibenz[b,f ]azepine (3) with NaNO3 in acetic anhydride/acetic acid gives 5-cyano-10-nitro-5H-dibenz[b,f ]azepine (4), which is treated with BF3 and powdered iron in acetic acid.

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: antagonism of anticonvulsant effect; avoid with St John’s wort.
Antiepileptics: concentration of perampanel reduced, also increased oxcarbazepine concentration.
Antimalarials: anticonvulsant effect antagonised by mefloquine.
Antipsychotics: antagonism of anticonvulsant effect.
Antivirals: concentration of rilpivirine and possibly daclatasvir and simeprevir reduced - avoid; possibly reduces dolutegravir concentration.
Ciclosporin: metabolism accelerated (reduced ciclosporin concentration).
Clopidogrel: possibly reduced antiplatelet effect.
Cytotoxics: concentration of imatinib reduced - avoid.
Guanfacine: possibly reduces guanfacine concentration - increase dose of guanfacine.
Oestrogens and progestogens: metabolism accelerated (reduced contraceptive effect).
Orlistat: possible increased risk of convulsions.
Tacrolimus: metabolism accelerated (reduced tacrolimus concentration).
Ulipristal: possibly reduces contraceptive effect.

Metabolism

Oxcarbazepine is rapidly and extensively metabolized to its primary metabolite, MHD, 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 excreted in the urine mainly as metabolites.

storage

Store at RT