Clinical Experience with Oxcarbazepine

Summary: Controlled studies of oxcarbazepine (OCBZ) and the largest of the open studies of OCBZ were reviewed. The overall results indicated that OCBZ has the same clinical effect as carbamazepine (CBZ) but causes fewer adverse effects. Studies of allergic toxicity seem to indicate that OCBZ may be tolerated in the majority of patients developing allergy towards CBZ. We concluded that OCBZ is a drug of first choice for the treatment of epilepsy.     

Oxcarbazepine: Mechanisms of Action

Summary: The antiepileptic drug (AED) oxcarbazepine (OCBZ) and its rapidly formed 10-monohydroxy metabolite (MHD) protect against electroshock-induced tonic hindlimb extension in rodents (ED₅₀ 14–21 mg/kg p.o.). Both stereoisomers of MHD also protect. As with carbamazepine (CBZ), these findings suggest clinical efficacy against generalized tonic-clonic and, to some extent, partial seizures. OCBZ (IC₅₀ 5 × 10⁸ M ), MHD (IC₅₀ 2 × 10^-8 M ) and CBZ (IC₅₀ 6 × 10^-7 M ) limit the frequency of firing of sodium-dependent action potentials by cultured mouse central neurons and reduce V _mix progressively in a use-dependent manner at concentrations below therapeutic plasma concentrations in OCBZ-treated patients. This suggests that blockade of voltagesensitive sodium channels could contribute to the antiepileptic efficacy of OCBZ. Blockade of penicillin-induced epileptiform discharges in hippocampal slices by MHD and its stereoisomers was diminished when the potassium channel blocker 4-aminopyridine was added to the bath fluid. This indicates that additional mechanisms of action, e.g., an effect on potassium channels, might be clinically important. In addition, both stereoisomers are equally responsible for the antiepileptic activity of the racemate, i.e., MHD, and are therefore likely to play a therapeutic role. Such actions could confer broad clinical utility on OCBZ.     

Cross-Reactive Skin Eruption with Both Carbamazepine and Oxcarbazepine

Summary: Oxcarbazepine (OCBZ), a 10-keto derivative of carbamazepine (CBZ) has been reported to have a similar range of efficacy and fewer unwanted effects than CBZ since it is a prodrug for the monohydroxy derivative (MHD). A cross-reactivity of only 1 in 4 has been reported between OCBZ and CBZ. For these reasons, we tried OCBZ with 3 consecutive patients with poorly controlled epilepsy who had had a therapeutic response to CBZ but in whom CBZ was discontinued because of serious skin reaction. Each patient had a similar skin response after exposure to only 600–900 mg OCBZ, which suggests a need to practice caution when substituting OCBZ for CBZ in patients known to have serious skin reaction to CBZ.     

Practical Aspects of the Use of Topiramate in Patients with Epilepsy

Summary: Practical recommendations for the treatment of patients with the new antiepileptic drug (AED) topiramate (TPM) were developed on the basis of review of the results of controlled and open studies of TPM reported to date and on postmarketing clinical experience with TPM at two specialized epilepsy clinics in the United Kingdom. Recommendations considered important for optimal utilization of TPM include dosage titration guidelines, options for managing side effects occurring early in treatment, advice concerning the withdrawal of concomitant AEDs, indications for discontinuation of TPM, and recognition of the need for adequate patient counseling.     

Clinical Pharmacology and Pharmacokinetics of Oxcarbazepine

Summary: Oxcarbazepine (OCBZ) is a new antiepileptic drug (AED) structurally related to carbamazepine (CBZ) but differing in several important aspects, notably metabolism and induction of metabolic pathways. Consequently, OXCB has fewer drug-drug interactions compared with CBZ. Absorption of OCBZ is rapid and complete. In animals it is responsible for the pharmacological effect. In humans, however, the parent compound is rapidly and extensively metabolized to a monohydroxy derivative (MHD), which is responsible for the therapeutic effect. Exposure to the MHD increases dose proportionally, and steady state is achieved after only three or four doses in a twice-daily regimen. When given with food, systemic exposure to MHD increases by about 17%. MHD is eliminated with a half-life of about 8–10 h. About 27% of the dose is recovered in the urine as unchanged MHD and a further 49% as a glucuronide conjugate of MHD. Results suggest that the kinetics of OCBZ should not be affected by impaired liver function. Impaired kidney function does not affect the kinetics of MHD; the glucuronide conjugate will, however, accumulate in these patients. The conversion of OCBZ to MHD is catalyzed by reductase enzymes, which are not subject to induction. Furthermore, OCBZ itself does not appear to induce the cytochrome P-450 family in general, although it does induce the P-450IIIA subfamily; which is responsible for the metabolism of estrogens and the dihydropyridine calcium-channel blockers (e.g., nifedipine, felodipine). In patients, linear and dose-proportional kinetics with no autoinduction of metabolism simplify OCBZ dosage adjustment.     

Possible Interaction Between Oxcarbazepine and an Oral Contraceptive

The effect of oxcarbazepine (OCBZ) on the kinetics of an oral contraceptive containing ethinyloestradiol (EE) and levonorgestrel (LNG) was investigated in 13 healthy female volunteers who had previously received the contraceptive for at least 3 months. After 15 days of the first study cycle, each subject received, in addition to the oral contraceptive, 300 mg OCBZ on day 16, 300 mg twice daily on day 17, and 300 mg three times daily from day 18 of the first cycle to day 18 of the next menstrual cycle. The area under the curve values for both EE and LNG decreased when OCBZ was given with the oral contraceptive (p = 0.006, analysis of variance). The results indicate that OCBZ, like most antiepileptic drugs (AEDs), decreases the bioavailability of EE and LNG, perhaps by affecting metabolism or protein binding.     

Hyponatremia Associated with Carbamazepine and Oxcarbazepine Therapy: A Review

Summary: Hyponatremia, an electrolyte disturbance usually without clinical significance, may sometimes lead to serious complications when overlooked or not treated appropriately. One cause of hyponatremia, the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, has been associated with some drugs, including carbamazepine (CBZ). Because of its antidiuretic effects, CBZ has been used successfully to treat diabetes insipidus centralis. Possible mechanisms for the antidiuretic effects of CBZ have been proposed. Altered sensitivity to serum osmolality by the hypothalamic osmoreceptors appears likely, but an increased sensitivity of the renal tubules to circulating ADH cannot be excluded. CBZ has led to hyponatremia in patients with epilepsy, neuralgia, mental retardation, and psychiatric disorders with a frequency varying from 4.8 to 40%. Oxcarbazepine (OCBZ), which is structurally related to CBZ, has shown similar hyponatremic effects, but whether hyponatremia occurs more often than with CBZ is not yet clear. Experience with OCBZ is still limited, and there is no definite explanation for a possible difference in antidiuretic potency. Most patients with CBZiOCBZ-induced hyponatremia are asymptomatic. In rare cases, water intoxication has been reported, necessitating treatment discontinuation.     

Oxcarbazepine (GP 47.680): A Possible Alternative to Carbamazepine?

A double-blind randomized crossover design trial of carbamazepine (CBZ) and oxcarbazepine (OCBZ) was performed with 48 in-patients with epilepsy. All were stabilized on polytherapy including CBZ and had at least two seizures per week. CBZ was replaced by the trial medication. Each trial period started with a titration, followed by a 12-week steady state. Concomitant medications were kept constant during the trial. The criteria for assessment were seizure fit frequency and severity; tolerability; hematology and blood chemistry; plasma levels of antiepileptic drugs; EEG; cardiovascular parameters; and treatment preference. The following differences regarding OCBZ were detected: 9% reduction of the total number of seizures, with a significant reduction of tonic-clonic (20%) and tonic (31%) seizures; increased alertness and concentration ability in five patients; an allergic skin reaction with CBZ that completely disappeared in two patients while receiving OCBZ; an increase of valproate and phenytoin plasma levels in a number of patients, probably caused by reduced enzyme induction; a slight but significant reduction of serum Na, not causing clinical symptoms; less seizures than in the CBZ period in 25 patients (52%); and a preference for OCBZ in 23 patients (48%). We consider OCBZ at least as effective as CBZ with a slightly better tolerability. In severe cases, the wider therapeutic window might improve seizure control.     

Anticonvulsant Action of Oxcarbazepine, Hydroxycarbamazepine, and Carbamazepine Against Metrazol-Induced Motor Seizures in Developing Rats

Summary: Antimetrazol effects of carbamazepine (CBZ, 5, 12.5, 25, or 50 mg/kg), oxcarbazepine (OCBZ, 5, 10, 30, or 60 mg/kg), and hydroxycarbamazepine (HCBZ, the main human metabolite of OCBZ, 10, 30, or 60 mg/kg) were studied in 7–, 12–, 18–, 25–, and/or 90-day-old laboratory rats. No drug tested affected the incidence of minimal (clonic) metrazol seizures (mMs) in animals aged ≥18 days; in rats aged 7 or 12 days in which mMs are rare under control conditions, the incidence of mMs was increased by lower doses of CBZ and HCBZ. All drugs tested specifically abolished the tonic phase of major generalized tonic-clonic seizures (MMs) in a dose-dependent manner. In addition, CBZ and OCBZ were able to suppress all phases of MMs in the two youngest groups (7-and 12-day-old). There were no marked differences among the three drugs tested (CBZ, OCBZ, and HCBZ) on their action against metrazol-induced seizures during ontogenesis of rats; i.e., all these drugs appeared to possess an identical profile of anticonvulsant action.     

Standard Approach to Antiepileptic Drug Treatment in the United Kingdom

Summary: In the United Kingdom, the question of whether to commence antiepileptic drug (AED) treatment remains controversial. Surveys indicate that 15% of patients are treated after a first seizure. Pediatricians often wait for a third or fourth seizure before treating, whereas clinicians who deal with adult patients are more likely to intervene early, largely because of concerns about driving and employment. Monotherapy is becoming the rule for the majority of patients. The four primary AEDs in the United Kingdom are carbamazepine and phenytoin (˜ 30% each), valproate (VPA; ˜25%), and phenobarbital (˜ 18%). For partial epilepsies, studies show few major differences in efficacy among these four AEDs. A first-line AED should be one, such as VPA, with a broad spectrum of activity that is easily managed by clinicians who may not have special expertise in the recognition of differing seizure types and epilepsy syndromes. Where differences in efficacy are marginal, comparative drug toxicity may be a major factor in AED selection. Most new AEDs have low toxicity profiles. With respect to discontinuation, pediatricians usually recommend a trial discontinuation period in most children who achieve a 1- or 2-year remission of epilepsy. For adults, however, overall relapse rates after discontinuation are – 40¹-50%; therefore, patients usually opt for long-term AED therapy.     

Long-Term Experience with Topiramate as Adjunctive Therapy and as Monotherapy in Patients with Partial Onset Seizures: Retrospective Survey of Open-Label Treatment

Summary: Because initial studies of new antiepileptic drugs (AEDs) are add-on trials in refractory patient populations, their effectiveness as monotherapy is usually not apparent until relatively later in their development programs. The novel AED topiramate (TPM) has been found efficacious as adjunctive therapy in controlled, randomized trials in adults with partial onset seizures. We report a retrospective analysis of TPM as AED monotherapy in 214 patients from five centers who received TPM in investigational trials. Of this total, 136 (64%) were still receiving TPM at the time of the analysis, with a mean treatment duration of 2.5 years. One-third of the patients have been successfully converted to TPM monotherapy, and 62% of those converted have been seizure-free for at least 3 months. The results of this analysis suggest that TPM may prove to be a valuable new AED for both monotherapy and add-on therapy in partial onset epilepsy.     

Oxcarbazepine Does Not Affect the Anticoagulant Activity of Warfarin

The possible interaction of the antiepileptic drug oxcarbazepine (OCBZ) on the anticoagulant effect of warfarin was investigated in 10 healthy male volunteers. After reaching steady-state conditions by repeated administration of warfarin, the prothrombin time (Quick value) was assessed before and after single (600 mg) and multiple dosing (450 mg twice daily in 1 week) of OCBZ. In 7 of the 10 volunteers with evaluable data, the prothrombin time was not significantly different (paired t test) from baseline either after single (p = 0.299) or repeated dosing (p = 0.333), indicating that OCBZ does not interact to any relevant extent with the hypothrombinemic effect of warfarin.     

Lamotrigine in Treatment of 120 Children with Epilepsy

Summary: One hundred twenty children aged 10 months to 16 years 9 months were included in three studies with lamotrigine (LTG): a single-blind study (n = 60), a pharmacokinetic study (n = 23), and a compassionate group (n = 37). At 3 months, 11 patients had become seizure-free and 34 had >50% decrease in seizure frequency. The best results involved absence epilepsy, Lennox-Gastaut syndrome (LGS), and other symptomatic generalized epilepsy. Forty-two patients were followed > 1 year, 22 for a mean of 2.2 years, and there was no significant increase in seizure frequency as compared with 3-month follow-up. Fourteen patients became seizure-free for >6 months; all except 1 had generalized epilepsy. For 12 patients, treatment could be reduced to monotherapy, but for those with valproate (VPA) comedication LTG dosage had to be increased; 25% of patients with VPA monotherapy exhibited skin rash, appearing 3–18 days after starting LTG. For 4 patients, LTG could be reintroduced after VPA was withdrawn. Ten patients had ataxia and/or drowsiness and 2 had vomiting. For all other patients, tolerance was excellent.     

Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

PURPOSE: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives. METHODS: Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mg/day) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 microg ethinylestradiol (EE) and 250 microg levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle. RESULTS: Compared with placebo, areas under the plasma concentration curves (AUC(0-24h, geometric means) decreased by 47% for both EE (from 1,677 to 886 pg.h/ml; p < 0.01) and LN (from 137 to 73 ng.h/ml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < 0.01), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p < 0.01). CONCLUSIONS: OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.     

Investigational Antiepileptic Drugs for the Treatment of Childhood Seizure Disorders: A Review of Efficacy and Safety

Summary: Pediatric epileptology is very different from adult epileptology. Although some epileptic disorders occur in both children and adults (e.g., localization-related epilepsy with complex partial seizures and primary generalized epilepsy with tonic-clonic seizures), other disorders can be called the catastrophic epilepsies of childhood (e.g., infantile spasms and the Lennox-Gastaut syndrome). They occur, or at least begin, exclusively in childhood and are often associated with mental retardation. Many of these pediatric disorders are notoriously unresponsive to currently available antiepileptic drugs (AEDs). Although there are undoubtedly many reasons for this, one possible explanation is that the methods used to screen potential AEDs use animal models of adult epilepsy. No screening program uses an animal model of seizures that begin during development and lead to functional decline.     

Seizures with Clonazepam: Discontinuation and Suggestions for Safe Discontinuation Rates in Children

Clinical characteristics of clonazepam (CZP) discontinuation seizures were clarified from 17 patients who developed seizure exacerbation after rapid discontinuation, including abrupt discontinuation, reduction, or replacement with nitrazepam (NZP). Safe discontinuation rates of CZP were estimated by comparing these patients with 23 patients without CZP discontinuation seizures. The seizures consisted of status epilepticus or frequent attacks of generalized tonic-clonic seizures (GTC) or non-GTC, and the first attack of GTC. Incidence did not differ significantly between CZP-effective cases and CZP-ineffective cases at discontinuation. The reasons for abrupt discontinuation included adverse effects, insufficient efficacy, difficulty in taking CZP owing to pneumonia, or carelessness of the doctors or the families. Seizure exacerbation occurred 1–6 days after CZP discontinuation. Most of the problems improved with readministration of the original or smaller dosages of CZP or of NZP in an amount threefold or more greater than the original CZP dose. Safe discontinuation rates were estimated to be ≤0.04 mg/kg for abrupt discontinuation, ≤0.04 mg/kg/ week for reduction, and replacement with NZP of 2.5 or more times the original amount of CZP. These safe discontinuation rates were prospectively confirmed by 84 cases of CZP discontinuation in 54 other patients, and no seizure exacerbation occurred with these discontinuation rates.     

Felbamate in the Treatment of Lennox-Gastaut Syndrome: Results of a 12-Month Open-Label Study Following a Randomized Clinical Trial

Summary: Felbamate (FBM) is a new antiepileptic drug (AED) that has been evaluated in partial seizures and in the Lennox-Gastaut syndrome (LGS). When tested against placebo in an add-on, randomized, double-blind trial in 73 children with LGS, FBM significantly reduced the frequencies of astatic (atonic) seizures and generalized tonic-clonic seizures plus total seizure counts. In addition, FBM-treated subjects improved significantly on a parent-rated global evaluation and had fewer injuries. Overall, ˜50% of subjects experienced a 50% or greater reduction in total seizure frequency and a dose-response relationship was apparent. The improvement that occurred in the double-blind study has been sustained for at least 12 months in subsequent open-label follow-up studies. In the first month of FBM treatment, 62% of the subjects who had previously received placebo had a reduction in total seizure frequency of >50%. By the 12-month follow-up point, approximately half of the patients had a 50% reduction in total seizure count. Astatic seizures responded even better, with two-thirds of patients having a reduction of >50% in astatic seizure frequency after 12 months of treatment. Based on adverse experience reports thus far, FBM appears to be well tolerated. FBM is the first drug to be shown effective in the LGS in randomized controlled trials. Although few subjects with LGS became seizure free, the frequency of the most severe seizure types decreased and the patients' global functioning improved.     

Hyponatremia induced by oxcarbazepine in children

We report the case of a 12-year-old girl with severe clinically relevant hyponatremia (118 mmol/l) and hypochloremia (81 mmol/l) during treatment with oxcarbazepine (OCBZ). The adverse effects were rapidly reversible after discontinuation of OCBZ and did not occur when exposed to carbamazepine. We reviewed the charts of 48 patients who received OCBZ as in-patients in our epilepsy centre and found hyponatremia in nine and hypochloremia in four. The mean sodium level of all patients was 139 mmol/l (range 118–150 mmol/l). We did not see any correlation between sodium or chloride levels and dose of OCBZ or blood serum level of the active metabolite 10-OH-carbazepine. We emphasize that children are at risk of developing electrolyte disturbances during treatment with OCBZ and thus the level of at least sodium should be monitored in those patients.