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Active ingredient: Oxcarbazepine - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Anticonvulsants

Dosage Forms

  • Suspension
  • Tablet (150 mg, 300 mg and 600 mg film coated)

Brands / Synonyms

Oxaprozin; Oxaprozine; Oxcarbamazepine; Oxcarbazepine (Subject to patent free); Trileptal; Trileptal

Indications

For use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults with epilepsy and as adjunctive therapy in the treatment of partial seizures in children ages 4-16 with epilepsy.

Pharmacology

Oxcarbazepine is structurally a derivative of carbamazepine, adding an extra oxygen atom to the benzylcarboxamide group. This difference helps reduce the impact on the liver of metabolizing the drug, and also prevents the serious forms of anemia occasionally associated with carbamazepine. Aside from this reduction in side effects, it is thought to have the same mechanism as carbamazepine - sodium channel inhibition - and is generally used to treat the same conditions.

Mechanism of Action

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.

Absorption

Completely absorbed following oral administration. Food has no effect on the rate and extent of absorption of oxcarbazepine.

Toxicity

Isolated cases of overdose with oxcarbazepine have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment.

Biotrnasformation / Drug Metabolism

Oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). MHD is metabolized further by conjugation with glucuronic acid.

Contraindications

Oxcarbazepine should not be used in patients with a known hypersensitivity to oxcarbazepine or to any of its components.

Drug Interactions

Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDís that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD.

Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP 3A4/5 by OXC and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP-2C19 by OXC and MHD, however, is clinically relevant.

In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine).

In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists and oral contraceptives, resulting in a lower plasma concentration of these drugs.

As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.

Antiepileptic drugs

Potential interactions between Trileptal and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 2:

Table 2: Summary of AED interactions with Trileptal

AED Co-administered

Dose of AED (mg/day)

Trileptal dose (mg/day)

Influence of Trileptal on AED Concentration (Mean change, 90% Confidence Interval)

Influence of AED On MHD Concentration (Mean change, 90% Confidence Interval)

Carbamazepine
400-2000
900
nc1 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital
100-150
600-1800
14% increase [CI: 2% increase, 24% increase] 25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin
250-500
600-1800
nc1,2 30% decrease [CI: 3% decrease, 48 % decrease]
>1200-2400 up to 40% increase3 [CI: 12% increase, 60 % increase]
Valproic acid
400-2800
600-1800
nc1 18% decrease [CI: 13% decrease, 40 % decrease]

    1- nc denotes a mean change of less than 10%
    2- Pediatrics
    3- Mean increase in adults at high Trileptal doses

In vivo, the plasma levels of phenytoin increased by up to 40%, when Trileptal was given at doses above 1200 mg/day. Therefore, when using doses of Trileptal greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbital level, however, is small (15%) when given with Trileptal.

Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29-40%).

No autoinduction has been observed with Trileptal.

Hormonal contraceptives

Co-administration of Trileptal with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study [1,2]. The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study. Therefore, concurrent use of Trileptal with hormonal contraceptives may render these contraceptives less effective. Studies with other oral or implant contraceptives have not been conducted.

Calcium Antagonists

After repeated co-administration of Trileptal, the AUC of felodipine was lowered by 28% [90% CI: 20-33].

Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD.

Other drug interactions

Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin wshow no evidence of interaction with either single or repeated doses of Trileptal.

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