Antiepileptic Drugs, 5th Edition

Oxcarbazepine

49

Adverse Effects

Günter Krämer MD

Medical Director, Swiss Epilepsy Center, Zurich, Switzerland

Whereas up to now all new antiepileptic drugs have failed to demonstrate superior efficacy in comparison with the established drugs, the risk:benefit ratio of at least some compounds has advantages. For oxcarbazepine (OXC), a ketoderivative of carbamazepine (CBZ), it is of special clinical interest that there is no major hepatic enzyme induction and no active epoxide metabolite, to which at least some of the adverse effects of CBZ have been attributed (1). Although OXC has a tolerability profile similar to that of CBZ, it is associated with a lower incidence of serious adverse effects such as severe allergic reactions (2,3). After >450,000 patient-years up to 2001 (4) and >20 years of experience with OXC (5,6), the spectrum of adverse effects is well known, and the risk of emerging new severe or potentially life-threatening adverse effects is likely to be low (7,8).

MOST COMMONLY OBSERVED ADVERSE EFFECTS

The data are presented for adults and children and for monotherapy or add-on-therapy. Hyponatremia is discussed separately.

Adults with Monotherapy

The most commonly observed adverse effects (>10% of patients) associated with OXC monotherapy in adults are somnolence or sedation, headache, dizziness, nausea, vomiting, fatigue, abnormal vision, and diplopia. In general, OXC was well tolerated in five clinical monotherapy trials in comparison with phenytoin (PHT), valproate (VPA), or placebo (9, 10,11, 12, 13) (Table 49.1). Although ≤90% of the patients who received at least one dose of OXC reported adverse experiences, <10% withdrew from treatment because of these effects. Reasons for premature discontinuation included rash (9, 10, 11, 12, 13), postictal psychosis (9,13), ataxia (9), suicide attempt with OXC (10), or headache and dizziness (11,12). However, in one trial, all dropouts occurred during the tapering phase in which concomitant antiepileptic drugs were discontinued and before OXC monotherapy was reached (9).

The time to premature discontinuation of treatment because of adverse experiences was significantly in favor of OXC compared with PHT (p = .02) in one study (10), but there was no significant difference compared with VPA (11). Overall, OXC was better tolerated than PHT (particularly with respect to gum hyperplasia, tremor, diplopia, and nystagmus), and VPA (particularly with respect to tremor, weight gain, alopecia, and headache).

In a retrospective analysis of 947 outpatients with epilepsy, as few as 33% of OXC treated patients reported adverse effects, with 18% discontinuing treatment prematurely (14). Most patients (93%) were aged ≥15 years and received OXC at an average dosage of 18 mg/kg/day as monotherapy (n = 597) for a mean duration of 23 months. Among the patients who received OXC as monotherapy, rash (7%), fatigue (5%), dizziness (4%), and sedation (4%) were the most common side effects. Half of the patients who experienced rash had previously had allergic reactions to CBZ (see the later discussion of skin rashes in this chapter). Central nervous system-related adverse effects associated with OXC monotherapy were usually moderate and less frequent than those in patients receiving adjunctive therapy, yet they were more often rated as severe (in 26% versus 15% of patients). The rate of discontinuation of treatment because of adverse effects was similar in both groups (14).

Two controlled double-blind comparisons of OXC with CBZ with equipotent dosages (OXC:CBZ = 1.5:1) in patients with epilepsy indicated a similar incidence of adverse reactions for both drugs (15,16). However, in the largest randomized comparison to date, OXC was associated with significantly fewer severe adverse effects, defined as events requiring drug withdrawal (14% for OXC versus 26% for CBZ). Rash was the most severe adverse effect in 16 of 25 patients withdrawn from CBZ and in nine of 13 patients withdrawn from OXC (17).

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TABLE 49.1. PERCENTAGES OF PATIENTS WHO EXPERIENCED ADVERSE EVENTS IN RANDOMIZED MONOTHERAPY PARALLEL-GROUP TRIALS COMPARING OXCARBAZEPINE WITH PHENYTOIN, VALPROATE, AND PLACEBO

Reference Beydoun et al. (9) Bill et al. (10) Christe et al. (11) Sachdeo et al. (12) Schachter et al. (13) OXC OXC OXCb PHTb OXCc VPAc OXCd PL OXCe PLe Adverse Events (2,400 mg/da, n = 41) (300 mg/daya, n = 46) (n = 136) (n = 142) (n = 128) (n = 121) (n = 32) (n = 35) (n = 51) (n = 51) Somnolence 29.3 4.3 30.1 28.9 14.8 19.8 6.3 11.4 16 0 Headache 22.0 8.7 14.7 19.0 10.2 17.4 15.6 11.4 20 20 Dizziness 46.3 8.7 13.2 15.5 10.2 11.6 25.0 2.9 18 12 Nausea 29.3 8.7 9.6 11.3 8.6 11.6 12.5 17.1 20 6 Vomiting 22.0 4.3 10 4 Fatigue 39.0 8.7 12.5 15.7 21.9 14.3 10 2 Rash 12.2 4.3 8.8 11.3 18f 8f Gum hyperplasia 1.5 12.7 Tremor 2.9 7.0 3.9 15.7 Diplopia 19.5 0 0.7 7.7 12 0 Apathy 11.5 10.6 Weight gain 12.5 21.5 Alopecia 8.6 17.4 Abnormal vision 17.1 2.2 OXC, oxcarbazepine; PHT, phenytoin; PL, placebo; VPA, valproate. Only events occurring in at least 10% of patients in at least one arm of the trial are reported. a OXC 2,400 or 300 mg/day in adults with refractory partial or generalized seizures (short-term trial). b OXC 600 to 2,100 mg/day or PHT 100 to 650 mg/day in previously untreated adults with partial seizures. c OXC 450 to 2,400 mg/day or PHT 150 to 800 mg/day in previously untreated adults with partial seizures. d OXC 1,200 mg/day or PL in untreated patients with recent onset epilepsy (short-term trial). e OXC 2,400 mg/day or PL in patients with refractory partial and/or generalized seizures (short-term trial). f These patients experienced pruritus.

Adults with Add-on Therapy

The most commonly reported adverse effects in adults with OXC add-on therapy are dizziness, somnolence, sedation, headache, fatigue, nausea, vomiting, ataxia, nystagmus, and abnormal gait.

OXC was well tolerated in two retrospective studies involving the long-term use of OXC adjunctive therapy (14,18). In 757 predominantly adult patients (age range, 7 to 91 years) with severe focal (66%) and/or generalized seizures, as few as 100 adverse effects were reported, which were severe in 0.9% of patients, and only 10 patients (1.3%) discontinued treatment because of them. Most patients were treated for 2 to 6 years, with dosages between 150 and 3,600 mg/day (18). Along with dizziness, headache, nausea, and vomiting, hyponatremia was also a common adverse effect (see later).

In a long-term monitoring study, 164 patients who had previously been treated with CBZ were switched to OXC therapy (monotherapy and adjunctive therapy were not differentiated) because of adverse effects and/or intolerability during CBZ therapy (19). Eighteen percent became free of adverse effects, and in 60% of the patients, symptoms became tolerable. The adverse effects most likely to resolve on switching to OXC were undetermined skin reactions (rashes, pruritus, eczema), allergic reactions, and a combination of malaise, dizziness, and headache.

In a large randomized, four-arm, double-blind, placebo-controlled parallel trial with three different OXC doses in 694 patients (15 to 65 years of age) with at least four seizures per month (20), the most common adverse effects were related to the central nervous system (dizziness, headache, somnolence, ataxia, nystagmus, abnormal gait) and the digestive system (nausea, vomiting, abdominal pain). The highest adjunctive dosage of OXC (2,400 mg/day) was associated with a very high proportion of patients (>65%) discontinuing treatment, mainly because of central nervous system-related adverse events. However, treatment was well tolerated in patients receiving OXC 1,200 mg/day (20).

A Cochrane review calculated the overall odds ratio and corresponding confidence interval (CI) for treatment withdrawal in the two largest add-on trials representing 961 randomized patients—694 adults (20) as well as 267 children (21); see later for details—as 2.17 (95% CI, 1.59, 2.97). The significantly associated figures for individual adverse effects were 4.32 for diplopia (99% CI, 2.65, 7.04), 3.05 for dizziness (99% CI, 1.99, 4.67), 2.93 for ataxia (99% CI, 1.72, 4.99), 2.88 for nausea (99% CI 1.77, 4.69), 2.55 for somnolence (99% CI, 1.84, 3.55), and 1.80 for fatigue (99% CI, 1.02, 3.19) (22).

In the context of polytherapy, OXC has a lower enzyme-inducing activity compared with CBZ, PHT, or barbiturates. When one of the latter drugs is substituted with OXC, cessation of enzyme induction may lead to increased serum levels of certain comedications, with possible signs of intoxication. For example, in a study in patients receiving haloperidol, chlorpromazine, or clozapine, replacement of

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CBZ with OXC resulted within 2 to 4 weeks in a 28% to 200% increase in the plasma concentrations of these antipsychotic agents (all of which are known to be lowered by CBZ) and in the appearance of extrapyramidal symptoms (23).

Children with Monotherapy

In three of the five randomized, controlled trials that have studied effectiveness and tolerability in pediatric patients, OXC was initiated as monotherapy (12,13,24), the patients of another trial were converted to monotherapy with OXC (9), and the remaining trial was an add-on study in refractory patients (21). However, only two studies were restricted to pediatric patients (21,24), whereas the others involved adult patients as well. Common adverse effects in previously untreated children receiving OXC monotherapy are similar to those in adults: somnolence, headache, dizziness, nausea, apathy, and rash.

In a multicenter, randomized, double-blind, parallel-group trial comparing OXC with PHT in 193 children and adolescents with newly diagnosed epilepsy with at least two seizures in the last 6 months, the primary tolerability variable was a comparison of the time to premature discontinuation because of adverse effects (24). This was significantly longer for OXC (p = .002). OXC was better tolerated than PHT, particularly with respect to nervousness, dizziness, gum hyperplasia, hypertrichosis, and ataxia. In total, 82.3% of patients reported adverse experiences while receiving OXC compared with 89.4% of the PHT-treated group. Of these patients, two receiving OXC discontinued treatment because of rash, and 14 PHT recipients were withdrawn from treatment because of hypertrichosis, gingival hypertrophy, or rash. The physician's and patient's overall assessments of tolerability were significantly better in the OXC-treated group (p = .001 for physicians and p = .038 for patients).

Children with Add-on Therapy

The most common adverse events experienced by children (aged 1.2 to 17.9 years) undergoing add-on therapy with OXC were somnolence, headache, dizziness, vomiting, nausea, diplopia, fever, and ataxia (21,25). In a multinational, multicenter, placebo-controlled, double-blind, parallel-group trial evaluation of the efficacy and tolerability of OXC as adjunctive therapy (30 to 46 mg/kg/day) to stable doses of up to two standard antiepileptic drugs, 267 children and adolescents (between 3 and 17 years of age) with inadequately controlled partial seizures were randomized (21). Ninety-one percent of patients receiving OXC and 82% of those receiving placebo reported adverse events. Fourteen patients (10%) receiving OXC discontinued treatment prematurely (mainly because of nausea, vomiting, and rash) compared with 3% of the patients receiving placebo. Rash occurred in 4% of the OXC group and in 5% of the placebo group, and two of the four patients who discontinued OXC treatment because of maculopapular and erythematous rash received CBZ as concomitant medication (21).

Hyponatremia

Hyponatremia is usually defined as a serum sodium level <135 mmol/L and is a well-known adverse effect of CBZ and OXC (16). In clinical studies, the incidence of this effect varies between 5% and 40% for CBZ (26) and between 23% (14) and 73.3% (27) for OXC. In most patients, hyponatremia is asymptomatic, and discontinuation of OXC is only rarely necessary. Clinical symptoms of acute hyponatremia usually occur with sodium levels <125 mmol/L and may include headache, nausea, vomiting, tremor, delirium, increased seizure frequency, and coma (28). The symptoms of chronic hyponatremia are more subtle and include anorexia, cramps, personality changes, gait disturbance, stupor, nausea, and vomiting, but the condition may be accompanied by increased seizures and psychosis as well (29).

In a large retrospective series of OXC therapy (14), a shift to abnormal (not further defined) serum sodium levels was observed in 23% of the 350 patients (from a total population of 947) with available laboratory test data. However, only four patients (0.4% of the total population) discontinued treatment because of hyponatremia.

The manufacturer's prescribing information states that hyponatremia with a serum sodium <125 mmol/L developed in 2.5% of OXC-treated patients in the 14 controlled monotherapy and adjunctive therapy studies conducted to date, compared with no patients who received placebo or active controls (CBZ, phenobarbital, PHT, or VPA). Most hyponatremic patients were asymptomatic, but patients in clinical trials were frequently monitored, and some had their OXC dosage reduced or discontinued. The manufacturer's database included records of 1,966 patients with epilepsy aged between 2 and 88 years who had been treated for 20 months with OXC 600 to 1,800 mg/day (4). Serum sodium levels were <135 mmol/L in 423 patients (21.5%) and <125 mmol/L in 54 patients (2.7%). Generally, patients with hyponatremia recovered once OXC therapy was stopped. The incidence of symptoms suggestive of hyponatremia was similar among all patients, irrespective of sodium levels (4).

In a study of 15 patients with epilepsy refractory to multidrug therapy in which OXC was substituted for CBZ, mean plasma sodium levels decreased from 137.5 to 128.5 mmol/L. Imposed restriction of fluid intake may have minimized the degree of hyponatremia in these patients (27). In another study, serum sodium levels decreased significantly in six of 10 male patients changed from CBZ to OXC (30). Although it had been proposed that both drugs cause an increase in plasma arginine vasopressin secretion or have a direct tubular effect in the kidney, this study suggested that

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OXC-induced hyponatremia is not caused by changes in serum aldosterone or atrial natriuretic peptide.

The degree of hyponatremia seems to be related to the dose and to the serum concentration of the active monohydroxy derivative (MHD) of OXC, with an increased incidence at OXC doses >25 to 30 mg/kg per day (27,31,32). Increasing age has also been identified as a risk factor for OXC-induced hyponatremia. In an analysis of the manufacturer's database (33), marked hyponatremia (sodium levels <125 mmol/L) increased with age from 0% at <6 years and 0.5% between 6 and 17 years to 3.4% between 18 and 64 years and 7.3% at >65 years. In a study of 144 randomly selected patients with epilepsy (3), female patients were found to have lower serum sodium levels than male patients (monotherapy: 134 versus 137.6 mmol/L, p < .05; adjunctive therapy 131.3 versus 137.9 mmol/L, p < .001). Other authors described an increased incidence of hyponatremia in patients receiving polytherapy (34) or in patients taking sodium-lowering drugs such as diuretics (35). Because in monotherapy trials the incidence of hyponatremia was highest in a 10-day study with a 2-day titration period (13), fast titration may be another risk factor (3).

Appropriate management of symptomatic OXC-induced hyponatremia includes restriction of fluids and dose reduction or discontinuation. In case of discontinuation, switch to CBZ or PHT is preferable. Rapid correction of hyponatremia with hypertonic saline is rarely if ever required and is associated with risks greater than those of hyponatremia itself (7). There is no evidence of the effectiveness of additional intake of sodium chloride in the prevention or amelioration of hyponatremia. Some clinicians routinely monitor serum sodium in patients on OXC and regard values of <130 mmol/L as unacceptable (36).

TABLE 49.2. PERCENTAGES OF PATIENTS WHO EXPERIENCED ADVERSE EVENTS IN A RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL-GROUP TRIAL COMPARING DIFFERENT DOSAGES OF OXCARBAZEPINE GIVEN AS ADJUNCTIVE THERAPY IN ADULTS WITH REFRACTORY PARTIAL EPILEPSY

Adverse Event OXC (600 mg/day, n = 168) OXC (1,200 mg/day, n = 177) OXC (2,400 mg/day, n = 174) PL (n = 173) Reporting an adverse event 83.9 90.4 97.7 76.3 Dizziness 25.0 31.6 42.5 12.7 Headache 32.1 27.1 23.0 23.7 Somnolence 19.6 27.1 32.2 11.6 Ataxia 9.5 17.5 32.2 5.2 Nystagmus 6.5 20.3 23.6 4.0 Abnormal gait 5.4 9.6 14.9 1.2 Tremor 3.6 7.9 14.4 4.0 Vomiting 13.1 24.9 33.3 4.6 Nausea 14.9 24.3 28.2 8.1 Abdominal pain 9.5 12.4 8.0 4.6 Diplopia 13.7 30.5 39.1 4.6 Abnormal vision 6.5 13.6 17.2 4.0 Vertigo 6.5 11.3 13.8 2.3 Fatigue 14.9 11.9 14.9 6.9 Viral infection 11.9 9.6 5.7 13.9 OXC, oxcarbazepine; PL, placebo. Only events occurring in at least 10% of patients in at least one arm of the trial are reported (20).

Skin Rashes

The incidence of allergic rashes for OXC is lower than for CBZ (15,37). In the prospective Scandinavian multicenter study, rashes led to early discontinuation in 10% of patients given OXC and in 16% of those given CBZ, despite low starting doses of both drugs (OXC, 300 mg; CBZ, 200 mg) and a slow titration rate (17). Cross-allergies in patients with known rashes from CBZ are in the range of 25% to 31% (19,38,39), and this does not exclude the possibility of three consecutive patients' experiencing a cross-reaction (12). Most rashes occurs in the first month of treatment. Some authors have recommended patch tests or lymphocyte proliferation assays before starting OXC in patients with known CBZ-induced skin problems (19,32). Finally, successful desensitization has been described in a patient with a rash caused by OXC (41).

Effects on Cognition

The cognitive side effects of OXC have been little investigated up to now. In a study in patients undergoing initiation of antiepileptic drug treatment, no cognitive function changes were detected 4 months after starting OXC monotherapy compared with baseline (12). In another study in patients receiving long-term OXC monotherapy, cognitive side effects were similar to those seen in patients taking PHT (43).

In a double-blind, three-phase, crossover study, 12 healthy volunteers received OXC 150 mg twice daily, OXC

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300 mg twice daily, or placebo for 1 week each. In this study, OXC was associated with a slight stimulant effect, documented by improved performance on a focused attention task, increased manual writing, and enhanced alertness and clearheadedness (44). By contrast, in patients with epilepsy, increased sedation and decreasing test results were observed 2 to 6 hours after intake of OXC (45). However, as already stated, other studies did not find significant changes after 4 months of OXC monotherapy (42) or after 6 to 12 months monotherapy in comparison with PHT (43).

Dose Dependency

For some adverse effects of OXC, a dose dependency has been described. In the large add-on trial in adults comparing 600 mg, 1,200 mg, and 2,400 mg/day OXC (20), most of the adverse effects were dose related; these included dizziness, diplopia, somnolence, vomiting, nausea, ataxia, nystagmus, abnormal vision, vertigo, and abnormal gait (Table 49.2). In a survey of children and adolescents treated with OXC, it was stated that adverse effects appeared in most patients at blood levels of MHD ~35 to 40 mg/L (25). As discussed earlier, the incidence of hyponatremia is also related to OXC dose and serum drug levels (27,31,32).

Time Dependency

With the exception of the well-known prevalence of allergic rashes during the initiation of treatment, there are no other data on a time dependency of adverse effects of OXC.

LESS COMMON BUT CLINICALLY RELEVANT ADVERSE EFFECTS

Less common adverse effects of OXC include, in alphabetic order, abdominal pain, acne, agitation, alopecia, apathy, diarrhea, gum hyperplasia, laboratory abnormalities, nervousness, oculogyric crises, respiratory distress, tremor, and weight gain.

With the exception of hyponatremia, OXC-induced laboratory abnormalities are rare and are less common in comparison to CBZ (4,46). Single cases of pancytopenia and thrombopenia have been observed (47). As far as liver function tests are concerned, a trend toward slightly elevated values has been described by some investigators (14,16,48). In an open long-term study comparing OXC with CBZ and VPA in young girls with epilepsy, OXC as well as the other drugs did not affect linear growth or pubertal development, and OXC was not associated with weight gain. However, although fasting serum insulin and insulinlike growth factor binding protein 1 or 3 were not influenced by OXC (14.2 to 33.2 mg/kg/day), the levels of plasma insulinlike growth factor I (IGF-I) were increased, and this was attributed to increased hepatic synthesis of IGF-I. The clinical significance of this observation remains to be established (49). OXC induces the metabolism of steroid hormones such as ethinylestradiol and levonorgestrel (50).

After a switch from CBZ to OXC, a normalization of several laboratory values can be observed. This can be the case for some sex hormones such as dehydroepiandrosterone sulfate and sex hormone-binding globulin (SHBG) (51), serum thyroxine, free thyroxine and thyrotropin (52,53), total cholesterol (54), serum γ-glutamyltransferase activity, erythrocyte folate, serum vitamin B₁₂ levels, white blood cell count, and mean corpuscular volume of erythrocytes (55). OXC has been reported to increase the serum concentrations of testosterone, gonadotropins, and SHBG in men with epilepsy (56).

Oculogyric crises can be a particularly unusual side effect of both CBZ and OXC. A 31-year-old man developed oculogyric crises after starting treatment with OXC, and the frequency of these episodes correlated with the dosage of the drug (57). Similar episodes had occurred in the past after exposure to CBZ. The patient was implanted a vagus nerve stimulator, whose use led to disappearance of the oculogyric crises.

A computerized analysis of saccadic and smooth-pursuit eye movements in a double-blind crossover study after single doses of 600 mg OXC or 400 mg CBZ in six healthy male volunteers demonstrated that OXC had weaker effects on the maximum saccade peak velocity and the typical target velocity (58).

POTENTIALLY LIFE-THREATENING ADVERSE EFFECTS

According to the manufacturer's database, serious adverse effects were observed in 326 of 2,486 (13.1%) OXC-treated patients with epilepsy, resulting in a total of 411 events. Disorders of gait, balance and coordination, hyponatremia, seizures, and rash were the adverse events most frequently considered to be related to OXC (4).

MANIFESTATIONS AND MANAGEMENT OF OVERDOSE

A total of six patients (all suicide attempts) took overdoses of OXC during the clinical trials, the maximum estimated dose taken being 24 g (4). Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatremia, ataxia, and nystagmus. All patients recovered with symptomatic and supportive treatment. There is no specific antidote. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.

Because of only minor removal of the major OXC metabolite MHD during a series of six plasmaphereses in a

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13-year-old boy taking 2,550 mg OXC/day (mean amount of MHD removed per plasmapheresis of less than 80 mg, or 3% to 4% of the daily dose), plasmapheresis was considered to be unlikely to be of therapeutic benefit in the treatment of OXC overdose (59).

PREGNANCY

The clinical experience with OXC in pregnant women is minimal up to now, and therefore the teratogenic potential of this drug in humans is virtually unknown. Up to 2001, 47 pregnancies have been documented in the manufacturer's database. There were 25 pregnancies reported in the primary database, two in named patient programs and 20 in postmarketing experience after exposure to OXC in utero. Of these 47 pregnancies, delivery of 20 healthy babies was documented. There were 13 abortions, five infants with malformations (three lip-facial-palatal clefts, a facial dysmorphia, and a case with unspecific cardiac abnormalities), and the outcome was unknown for the remaining seven (4).

USE IN SPECIAL POPULATIONS

Limited experience with OXC in treatment of early childhood epilepsy did not result in any special adverse effects. Hyponatremia (<132 mmol/L) was observed in 15% in a series of 53 children <7 years old; all but two patients were asymptomatic and needed no dose adjustments. Based on their observations, the authors of this study suggested that the risk of symptomatic hyponatremia may increase when children contract an infection or have prolonged seizures (60).

In a retrospective analysis of 40 children and adolescents with intellectual disability, most of whom were receiving polytherapy, OXC was associated with adverse effects in 16 (40%) patients, which led to dose reduction or discontinuation in eight (20%). Hyponatremia (defined as at least one level <132 mmol/L) was observed in 24% (61).

A 28-year-old patient with porphyria cutanea tarda who could not tolerate CBZ (resulting in elevation of transaminases as well as pruritus and erythema) was successfully treated with OXC (62). Because OXC retains some enzyme inducing activity, however, great caution should be used in prescribing this drug in patients with porphyrias.

Because the incidence of symptomatic OXC-induced hyponatremia is increased in elderly patients (especially women), in patients comedicated with diuretics, desmopressin, or nonsteroidal antiinflammatory agents, and in patients with renal disease, OXC is not a drug of first choice for these populations. If it is used, serum sodium concentrations should be monitored, at least in those patients at special risk or with symptoms likely related to hyponatremia (e.g., somnolence, nausea, vomiting, headache, confusion) (63).

CONCLUSION

Mainly because of its improved tolerability OXC, is a good candidate to replace CBZ as a drug of first choice in the treatment of focal seizures with or without secondary generalization. Direct comparisons of OXC and CBZ in patients with newly diagnosed epilepsy indicate that the two compounds are equally effective, but OXC may be associated with fewer adverse effects. Allergic skin reactions are less common with OXC, and the reduced propensity of OXC to induce oxidative metabolism may facilitate the attainment of therapeutic serum concentrations of comedications vulnerable to enzyme induction such as VPA. A systematic review and meta-analysis comparing the results of add-on trials of OXC and the other new antiepileptic drugs levetiracetam, remacemide, and zonisamide in drug-resistant localization-related epilepsy in children and adults ranked OXC as second after levetiracetam in terms of favorable responder and withdrawal rates (64). The only disadvantage of OXC in comparison with CBZ regarding adverse effects is the more pronounced hyponatremia. In addition, physicians in those European and other countries where a new formulation has recently been introduced have to be aware of the risk of increased adverse effects resulting from faster absorption and higher serum drug concentrations (65).

REFERENCES

1. Patsalos PN, Sander JWAS. Newer antiepileptic drugs: towards an improved risk-benefit ratio. Drug Saf1994;11:37-67.
2. Grant SM, Faulds D. Oxcarbazepine: a review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. Drugs1992;43:873-888.
3. Wellington K, Goa KL. Oxcarbazepine: an update of its efficacy in the management of epilepsy. CNS Drugs2001;15:137-163.
4. Novartis Pharmaceuticals. Data on file. Basel, 2001.
5. Rai PV. Clinical trial for the estimation of anticonvulsive properties and side reactions of a new drug: ketocarbamazepine. In: Wada JA, Penry JK, eds. Advances in epileptology: the Xth Epilepsy International Symposium.New York: Raven Press, 1980:357 (abst).
6. Krämer G. Oxcarbazepin: ein neues Antiepileptikum zur Monound Kombinationstherapie. Aktuelle Neurol2000;27.
7. Schmidt D, Sachdeo R. Oxcarbazepine for treatment of partial epilepsy: a review and recommendations for clinical use. Epilepsy Behav2000;1:306-405.
8. Schmidt D, Arroyo S, Baulac M, et al. Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view. Acta Neurol Scand2001;104:167-170.
9. Beydoun A, Sachdeo RC, Rosenfeld WE, et al. Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, doubleblind, clinical trial. Neurology2000;54:2245-2251.
10. Bill PA, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res1997;27: 195-204.

P.485

11. Christe W, Krämer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res1997;26: 451-460.
12. Sachdeo RC, Edwards K, Hasegawa H, et al. Safety and efficacy of oxcarbazepine 1200 mg/day in patients with recent onset partial epilepsy. Neurology1999;52[Suppl 2]:A391(abst).
13. Schachter SC, Vazquez B, Fisher RS, et al. Oxcarbazepine: a double blind, randomized, placebo-control, monotherapy trial in patients with epilepsy after presurgical evaluation of refractory partial seizures. Neurology1999;52:732-737.
14. Friis, ML, Kristensen O, Boas J, et al. Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment. Acta Neurol Scand1993;87:224-227.
15. Houtkooper MA, Lammertsma, A, Meyer JWA, et al. Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine? Epilepsia1987;25:693-698.
16. Reinikainen KJ, Keränen T, Halonen T, et al.. Comparison of oxcarbazepine and carbamazepine: a double blind study. Epilepsy Res1987;1:284-289.
17. Dam M, Ekberg R, Løyning Y, et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy.Epilepsy Res1989;3:70-76.
18. Suter P, Nungässer A. Long-term data of patients treated with oxcarbazepine in Switzerland on a named-patient basis. Epilepsia1996;37[Suppl 4]:88-89(abst).
19. van Parys JAP, Meinardi H. Survey of 260 patients treated with oxcarbazepine (Trileptal) on a named-patient basis. Epilepsy Res1994;19:79-85.
20. Barcs G, Walker EB, Elger CE, et al. Oxcarbazepine placebo-controlled dose-ranging trial in refractory partial epilepsy. Epilepsia2000;41:1597-1607.
21. Glauser TA, Nigro M, Sachdeo R, et al. Adjunctive therapy with oxcarbazepine in children with partial seizures. Neurology2000;54:2237-2244.
22. Castillo S, Schmidt DB, White S. Oxcarbazepine add-on for drug resistant partial epilepsy (Cochrane Review). In: Cochrane Library1:2001. Oxford, updated software. Abstract available from the internet: www.update-software.com/abstracts/ab002028.-htm
23. Raitasuo V, Lehtovaara R, Huttunen MO. Effect of switching from carbamazepine to oxcarbazepine on the plasma levels of neuroleptics. Psychopharmacology1994;116:115-116..
24. Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res1997;27: 205-213.
25. Borusiak P, Korn-Merker E, Holert N, et al. Oxcarbazepine in treatment of childhood epilepsy: a survey of 46 children and adolescents. J Epilepsy1998;11:355-360.
26. van Amelsvoort T, Bakshi R, Devaux CB, et al. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia1994;35:181-188.
27. Pendlebury SC, Moses DK, Eadie MJ. Hyponatraemia during oxcarbazepine therapy. Hum Toxicol1998;8:337-344.
28. Steinhoff BJ, Stoll K-D, Stodieck SRG, et al. Hyponatremic coma under oxcarbazepine therapy. Epilepsy Res1992;11:67-70.
29. Johannessen AC, Nielsen OA. Hyponatremia induced by oxcarbazepine. Epilepsy Res1987;1:155-156.
30. Isojärvi JIT, Huuskonen UEJ, Pakarinen AJ, et al. The regulation of serum sodium after replacing carbamazepine by oxcarbazepine. Epilepsia2001;42:741-745.
31. Nielsen OA, Johannessen AC, Bardrum B. Oxcarbazepine-induced hyponatremia, a cross-sectional study. Epilepsy Res1988; 2:269-271.
32. Zakrzewska JM, Ivanyi L. In vitrolymphocytic proliferation by carbamazepine, carbamazepine-10,11-epoxide, and oxcarbazepine in the diagnosis of drug-induced hypersensitivity. J Allergy Clin Immunol 1988;82:110-115.
33. Sachdeo RC, Wassertein AD, D'Souza J. Oxcarbazepine (Trileptal) effect on serum sodium. Epilepsia1999;40[Suppl 7]:103.
34. Huuskonen UEJ, Pakarinen AJ, Moilanen E, et al. The role of gender and drug metabolites in carbamazepine- or oxcarbazepine-related hyponatremia. Epilepsia1998;39[Suppl 6]:126 (abst).
35. Huuskonen UEJ, Isojärvi JIT. Antiepileptic drugs and serum sodium. Epilepsia1997;38[Suppl 8]:89-90(abst).
36. Dasheiff R. Letter to the editor. Seizure2000;9:372.
37. Dam M, Østergaard LH. Oxcarbazepine (other antiepileptic drugs). In: Levy RH, Matson RH, Meldrum BS, eds. Antiepileptic drugs,4th ed. New York: Raven Press, 1995:987-995.
38. Dam M, Jakobsen K (Danish Oxcarbazepine Study Group). Oxcarbazepine in patients hypersensitive to carbamazepine. Acta Neurol Scand1984;70:223(abst).
39. Jensen NO, Danish Oxcarbazepine Study Group: Oxcarbazepine in patients hypersensitive to carbamazepine. In: Book of abstracts: 16th Epilepsy International Congress.Hamburg, 1985(abst).
40. Beran RG. Cross-reactive skin eruption with both carbamazepine and oxcarbazepine. Epilepsia1993;34:163-165.
41. Watts D, Bird J. Oxcarbazepine sensitivity treated by desensitivation [Letter]. J Neurol Neurosurg Psychiatry1991;54:376.
42. Sabers A, Møller A, Dam M, et al. Cognitive function and anticonvulsant therapy: effect of monotherapy in epilepsy. Acta Neurol Scand1995;92:19-27.
43. Aikia M, Kälviäinen R, Sivenius J, et al. Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: one year follow-up. Epilepsy Res1992;11:199-203.
44. Curran HV, Java R. Memory and psychomotor effects of oxcarbazepine in healthy human volunteers. Eur J Clin Pharmacol1993;44:529-533.
45. Gillham RA, McKee PJW, Brodie MJ. Oxcarbazepine and cognitive function after a single dose and during a double-blind placebo-controlled cross-over study. Epilepsia1993;34[Suppl 2]:122(abst).
46. Klosterskov Jensen P. Oxcarbazepine (Trileptal) in anti-epileptic polytherapy. Behav Neurol1990;3[Suppl 1]:35-39.
47. Ciba Geigy. Trileptal. Oxcarbazepine: a first line antiepileptic (product information).Basel: Ciba-Geigy, 1994.
48. Bülau P, Stoll KD, Fröscher W. Oxcarbazepine versus carbamazepine. In: Wolf P, Dam M, Janz D, et al., eds. Advances in epileptology. XVIth Epilepsy International Symposium.New York: Raven Press, 1987:531-536.
49. Rättyä J, Vainionpää L, Knip M, et al. The effects of valproate, carbamazepine, and oxcarbazepine on growth and sexual maturation in girls with epilepsy. Pediatrics1999;103:588-593.
50. Fattore C, Cipolla G, Gatti G, et al. Induction of ethinylestradiol and levonorgestrel metabolism by oxcarabazepine in healthy women. Epilepsia1999;40:783-787.
51. Isojärvi JIT, Pakarinen AJ, Rautio A, et al. Serum sex hormone levels after replacing carbamazepine with oxcarbazepine. Eur J Clin Pharmacol1995;47:461-464.
52. Isojärvi JIT, Airaksinen KEH, Mustonen JN, et al. Thyroid and myocardial function after replacement of carbamazepine by oxcarbazepine. Epilepsia1995;36:810-816.
53. Payne TA, Kothary S, Varma NK, et al. Serum sodium and thyroid function after replacement of carbamazepine with oxcarbazepine. Epilepsia1997;38[Suppl 8]:94(abst).
54. Isojärvi JIT, Pakarinen AJ, Rautio A, et al. Liver enzyme induction and serum lipid levels after replacement of carbamazepine with oxcarbazepine. Epilepsia1994;35:1217-1220.
55. Isojärvi JIT, Pakarinen AJ, Myllylä VV. Basic haematological parameters, serum gamma-glutamyl-transferase activity, and erythrocyte folate and serum vitamin B₁₂levels during carbamazepine and oxcarbazepine therapy. Seizure 1997;6:207-211.

P.486

56. Rättyä J, Turkka J, Pakarinen AJ, et al. Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology2001;56:31-36.
57. Gatzonis SD, Georgaculias N, Singounas E, et al. Elimination of oxcarbazepine-induced oculogyric crisis following vagus nerve stimulation. Neurology1999;52:1918-1919.
58. Zaccara G, Gangemi PF, Messori A, et al. Effects of oxcarbazepine and carbamazepine on the central nervous system: computerised analysis of saccadic and smooth-pursuit eye movements. Acta Neurol Scand1992;85:425-429.
59. Christensen J, Balslev T, Villadsen J, et al. Removal of 10-hydroxycarbazepine by plasmapheresis. Ther Drug Monit2001;23:-374-379.
60. Gaily E, Granström M-L, Liukkonen E. Oxcarbazepine in the treatment of early childhood epilepsy. J Child Neurol1997;12:-496-498.
61. Gaily E, Granström M-L, Liukkonen E. Oxcarbazepine in the treatment of epilepsy in children and adolescents with intellectual disability. J Intellect Disabil Res1998;42[Suppl 1]:41-45.
62. Gaida-Hommernick B, Rieck K, Runge U. Oxcarabzepine in focal epilepsy and hepatic porphyria: a case report. Epilepsia2001;42:793-795.
63. Arroyo S, Krämer G. Treating epilepsy in the elderly: safety considerations. Drug Saf2001;18.
64. Marson AG, Hutton JL, Leach JP, et al. Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review.Epilepsy Res2001;46: 259-270.
65. Edelbroek PM, Augustijn PB, de Haan GJ, et al. Change in oxcarbazepine (Trileptal) formulation is associated with more side effects and higher blood concentrations. J Neurol Neurosurg Psychiatry2001;71:708-709.