Efficacy and tolerability of Trileptal (oxcarbazepine) in epilepsy

Oxcarbazepine in the treatment of focal epilepsy

In the last decade, a number of new generation AEDs have entered clinical practice. On the one hand, this made it possible to improve the quality of medical care for patients with epilepsy, on the other hand, it acutely confronted doctors with the problem of choosing a drug in different situations: with newly diagnosed epilepsy, if it is necessary to switch to a second monotherapy, when selecting a rational combination therapy. According to the proposals of the Working Group on the draft new classification of 2001, the following forms of symptomatic and probably symptomatic (cryptogenic) focal epilepsy are identified: Limbic epilepsies: – mesial temporal lobe epilepsy with hippocampal sclerosis; – mesial temporal lobe epilepsy caused by a specific etiology; – other types of specific localization and etiology. Neocortical epilepsies: – Rasmussen syndrome; – hemiconvulsion-hemiplegia syndrome; – other types of specific localization and etiology; – migratory partial seizures of early infancy. Focal epilepsy is the most common form of the disease in adults (up to 60–70%), of which approximately half of the cases are temporal lobe epilepsy. Focal epilepsy is characterized by simple focal, complex focal and secondary generalized seizures, gelastic, hemiclonic seizures. Diagnosis of focal epilepsy is based on determining the focal onset of seizures based on descriptions of seizures, routine EEG data, video-EEG monitoring data, testing the patient during a seizure, and analysis of seizure EEG [18]. Long-term administration of AEDs is the mainstay of treatment for epilepsy. For newly diagnosed focal epilepsy in adults, priority is given to monotherapy. But only in 50–70% of cases is it possible to achieve remission on one drug. Moreover, the first monotherapy is only 50% successful. In addition, despite the introduction of new AEDs into practice, the problem of drug resistance remains acute [18]. In this regard, individual selection of AEDs is of great importance, ensuring a reduction in the frequency of seizures, minimizing the side effects of AEDs, preventing iatrogenic resistance, and improving the quality of life of patients. Since the 1960s, carbamazepine (CMZ) has been the main drug in the treatment of focal epilepsy in adults and a model for comparison in studies of new AEDs. Oxcarbazepine is a 10-keto analogue of carbamazepine. Oxcarbazepine was first licensed in Denmark as an antiepileptic drug in 1990 and registered in Russia in 2004. The antiepileptic effect of oxcarbazepine is exerted by its main metabolite, hydroxy-10,11-dihydro-5H-dibenzazepine-5-carboxamide (MHD - monohydroxy derivative). The main mechanism of action of MHD is the blockade of sodium channels, but others include effects on calcium and potassium channels. Unlike CMH, oxcarbazepine (OZ) is metabolized via cytochrome P450-dependent reductases and therefore lacks inducing effects on hepatic oxidase metabolism [20]. Also, during the biotransformation of OKZ, the formation of the epoxide metabolite, which is responsible for most of the side effects of ACM, does not occur [27]. OKZ does not cause autoinduction [10,13,20] and is characterized by high bioavailability (>95%) [13]. Monohydroxy derivative (MHD) has linear pharmacokinetics and a lower level of binding to plasma proteins compared to CMH [23]. The fact that it is MHD, and not OKZ, that is not an independent active agent is the basis for the relatively low toxicity in overdose. Thus, a tenfold increase in the OKZ content led to only a twofold increase in the MHD concentration [30]. When prescribing oxcarbazepine both in monotherapy and in combination therapy, the initial dose is 600 mg per day in two doses, with weekly titration of no more than 600 mg until the effect is achieved. But in a hospital setting, if necessary, it is possible to achieve a therapeutic dose within 24 hours [23]. Data from a number of controlled clinical studies show that oxcarbazepine is not inferior in effectiveness to carbamazepine, diphenine, valproate with better tolerability. The effectiveness of replacing other AEDs with oxcarbazepine monotherapy has also been confirmed. Currently, the drug is the first-line drug of choice for monotherapy, adjunctive therapy, and treatment of drug-resistant focal epilepsy in adults and children [4,23,26,31]. In addition, oxcarbazepine is the first of the new generation of drugs approved by the FDA for monotherapy of focal seizures, and the first drug in 25 years, approved in 2003 for use as monotherapy in children from 4 years of age [18]. In 2005, the journal Epilepsy & Behavior published the results of a survey of experts regarding the treatment of symptomatic localization-related epilepsy in adults [12]. Some recommendations based on this survey are presented below in Tables 1, 2, 3, which clearly demonstrate the modern view on the choice of AEDs. Thus, according to experts, of the new drugs, only oxcarbazepine is the most suitable for the treatment of focal epilepsy in simple and secondary generalized seizures. Oxcarbazepine is also recommended as a second monotherapy when switching from gabapentin, lamotrigine, levetiracetam, phenytoin, topiramate, valproate. Combinations of oxcarbazepine with levetiracetam, lamotrigine, topiramate, and valproate are considered rational. Transfer to monotherapy with oxcarbazepine in case of insufficient effectiveness and poor tolerability of other AEDs was accompanied by a statistically significant improvement in quality of life [22]. Transferring from CMH to monotherapy with oxcarbazepine is well tolerated by patients, leads to a decrease in the frequency or elimination of attacks and a decrease in side effects. It should be remembered that 200 mg of KMZ corresponds to 300 mg of OKZ. The transition from CMH to oxcarbazepine is also accompanied by normalization of neurophysiological parameters [6]. A decrease in side effects occurs in 3/4 of cases [23]. It is important that the transition from CMH to oxcarbazepine can be either gradual or almost instantaneous [2,3]. But a one-stage transition is most successful at doses of KMZ up to 800 mg/day. in other cases, slower titration is recommended [26]. Switching from CMH to oxcarbazepine is not justified when a rash appears due to the presence of cross-sensitivity, which is observed in 25% of cases [18,26]. In many cases, the interaction of OKZ with other drugs is not clinically significant, although OKZ can increase the concentration of phenytoin and reduce the concentrations of lamotrigine and topiramate [13]. The minimal activation potential of the cytochrome P450 system determines, on the one hand, the greater effectiveness of OKZ in duotherapy (for example, with valproate) compared to CMH [25], on the other hand, it may cause side effects due to increased blood concentrations of other drugs [ 13.28]. In such cases, monitoring of blood levels and dose adjustment of AEDs is necessary. Side effects are often transient and noted at the beginning of treatment [4,5]. The most important of them: headache, dizziness, weakness, nausea, drowsiness, ataxia, diplopia, hyponatremia. Among the side effects, hyponatremia should be noted, which occurs more often during treatment with oxcarbazepine than against the background of CMH. Thus, a decrease in sodium to a level of 128 mmol/l and below was observed in 12.4% of those treated with oxcarbazepine and in 2.8% of those treated with CMZ. In patients of older age groups and when taking oxcarbazepine in daily doses >30 mg/kg, the likelihood of developing hyponatremia is higher [8,17]. Hyponatremia is asymptomatic in most cases and is clinically manifested primarily by dysfunction of the central nervous system. The first signs are malaise, nausea, drowsiness, and later psychosis, epileptic seizures, and coma may develop. However, the need to monitor sodium levels only arises in the presence of kidney disease, concomitant use of drugs that cause hyponatremia (diuretics, oral contraceptives, NSAIDs), or when clinical signs occur [24]. Serious side effects include very rarely hypersensitivity syndrome to anticonvulsants and hematological disorders [18]. Activation of the group of isoenzymes CYP3A OKZ causes increased metabolism of oral contraceptives and a decrease in the concentration of ethinyl estradiol and levonorgestrel, so it is necessary to take contraceptives with a high estrogen content (50 mg) [27]. According to the literature, oxcarbazepine does not cause an increased risk of malformations when used alone during pregnancy (248 women) compared with population data, although further studies are needed to clarify the safety profile [16]. At the same time, there is evidence of an increase in MHD clearance during pregnancy, which can lead to a decrease in blood concentrations and disruption of drug remission, which necessitates the need to monitor MHD levels [14]. The effect of oxcarbazepine on reproductive endocrine function in men is dose-dependent: in doses up to 900 mg/day. The concentration of male sex hormones in the blood does not change; at higher doses, there is an increase in the level of testosterone, gonadotropins, and binding globulin. But unlike CMH, oxcarbazepine does not cause a decrease in the bioactivity of androgens [21]. Oxcarbazepine, like CMH, is contraindicated in absence seizures, myoclonic seizures, can cause their occurrence in case of erroneous prescription in idiopathic generalized epilepsy, and also cause the phenomenon of secondary bilateral synchronization in focal epilepsies. At the same time, the effect of OKZ on generalized tonic–clonic seizures is less dramatic than that of CMH [9,11]. Thus, oxcarbazepine is a new generation drug for the treatment of focal epilepsy, characterized by good efficacy, tolerability and a favorable pharmacokinetic profile.

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Oxcarbazepine-native

Monotherapy for epilepsy begins with the prescription of small doses, individually increasing them until the desired therapeutic effect is achieved.

It is advisable to determine the concentration of carbamazepine in plasma in order to select the optimal dose, especially in combination therapy.

When transferring a patient to carbamazepine, the dose of the previously prescribed antiepileptic drug should be gradually reduced until it is completely discontinued.

Sudden cessation of carbamazepine may trigger epileptic seizures. If it is necessary to abruptly interrupt treatment, the patient should be transferred to another antiepileptic drug under the cover of the drug indicated in such cases (for example, diazepam administered intravenously or rectally, or phenytoin administered intravenously).

Several cases of vomiting, diarrhea and/or decreased nutrition, convulsions and/or respiratory depression have been described in newborns whose mothers took carbamazepine simultaneously with other anticonvulsants (possibly these reactions represent manifestations of the “bruising” syndrome in newborns, hemorrhages in the form of petechiae or purples.

In most cases, a transient or persistent decrease in the number of platelets and/or leukocytes is not a harbinger of the onset of aplastic anemia or agranulocytosis. However, before starting treatment with carbamazepine, and periodically during treatment, clinical blood tests should be performed, including counting the number of platelets and, possibly, reticulocytes, as well as determining the concentration of Fe in the blood serum.

Non-progressive asymptomatic leukopenia does not require discontinuation, however, treatment should be discontinued if progressive leukopenia or leukopenia accompanied by clinical symptoms of an infectious disease occurs.

Before starting treatment, it is recommended to conduct an ophthalmological examination, including examination of the fundus with a slit lamp and, if necessary, measurement of intraocular pressure. If the drug is prescribed to patients with increased intraocular pressure, constant monitoring of this indicator is required.

It is recommended to stop drinking ethanol.

The drug in a prolonged form can be taken once, at night. The need to increase the dose when switching to retard tablets occurs extremely rarely.

Although the relationship between the dose of carbamazepine, its concentration and clinical efficacy or tolerability is very small, regular determination of carbamazepine concentrations may be useful in the following situations: with a sharp increase in the frequency of attacks; to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if there is a suspicion of impaired absorption of the drug; if toxic reactions are suspected if the patient is taking several drugs.

In women of reproductive age, carbamazepine should be used as monotherapy whenever possible (using the minimum effective dose) - the incidence of congenital anomalies in newborns born to women who received combined antiepileptic treatment is higher than in those who received each of these drugs as monotherapy.

When pregnancy occurs (when deciding whether to prescribe carbamazepine during pregnancy), it is necessary to carefully compare the expected benefits of therapy and its possible complications, especially in the first 3 months of pregnancy. It is known that children born to mothers with epilepsy are predisposed to disorders of intrauterine development, including malformations. Carbamazepine, like all other antiepileptic drugs, can increase the risk of these disorders. There are isolated reports of cases of congenital diseases and malformations, including spina bifida. Patients should be provided with information about the possibility of an increased risk of malformations and the opportunity to undergo antenatal diagnosis.

Antiepileptic drugs increase folic acid deficiency, which is often observed during pregnancy, which may increase the incidence of birth defects in children (additional folic acid intake is recommended before and during pregnancy). In order to prevent increased bleeding in newborns, it is recommended that women in the last weeks of pregnancy, as well as newborns, be prescribed vitamin K1.

Carbamazepine passes into breast milk; the benefits and possible undesirable effects of breastfeeding should be weighed against ongoing therapy. Mothers taking carbamazepine may breastfeed their infants, provided that the infant is monitored for possible adverse reactions (eg, severe drowsiness, allergic skin reactions).

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.