Antiepileptic Drugs, 5th Edition

Carbamazepine

23

Clinical Efficacy and USE in Epilepsy

Pierre Loiseau MD

Honorary Professor, Department of Neurology, Bordeaux Medical University, Bordeaux, France

The efficacy of carbamazepine (CBZ) in patients with epilepsy was first demonstrated in the early 1960s and the drug was licensed in Europe soon after its discovery. The threat of serious adverse reactions (hematopoietic disturbances) delayed its use in North America. It was later demonstrated that the risk had been exaggerated. Along with valproic acid (VPA), CBZ belongs to the second generation of anticonvulsants, considered as having less neurotoxicity than older drugs such as phenytoin (PHT), phenobarbital (PB), and primidone (PRM), and it has been increasingly prescribed as a first-line drug. With the introduction of many new antiepileptic drugs (AEDs) in the 1990s, the question now is its place in a wider armamentarium of antiepileptic medication.

SPECTRUM OF EFFICACY

Evidence supporting the efficacy of CBZ as an anticonvulsant is derived from a host of studies with various designs. Some of these studies are summarized here.

Randomized, Controlled Trials

CBZ effectivness has been compared with that of a placebo or of active drugs, either alone or as an add-on medication.

Carbamazepine versus Placebo

CBZ or placebo was added for 3-week periods to baseline therapy of PB and PHT in 37 hospitalized adult patients with intractable psychomotor epilepsy. Secondarily generalized seizures were reduced by 55% and psychomotor seizures by 83% when the patients were on CBZ (1). Twenty-three difficult-to-control outpatients of all ages with grand mal or psychomotor seizures received CBZ and placebo for 3 months each. The preexisting medication was unchanged, but the CBZ dosage was increased, according to tolerance, up to 1,200 mg; complete control was not achieved in any, but ≥50% improvement occurred in 12 patients (2).

Carbamazepine versus Phenytoin

CBZ and PHT were compared in 24 adult epileptic patients with behavior disorders. They received the two drugs as sole medication, each for a 6- month period; no significant difference was found between the two drugs with regard to efficacy, but CBZ, compared with PHT, reduced significantly the severity of personality disorders (3). Thirty-eight patients (>12 years of age) with psychomotor seizures (31 previously treated) received CBZ or PHT as sole medication, each for 16 weeks. The effect of both drugs was the same, but some patients, however, responded better either to CBZ or to PHT (4). CBZ and PHT as sole drug were given to 47 adult outpatients with moderately severe seizure disorders (5). This double-blind study confirmed the conclusions of a pilot study (6): Both drugs were approximately equally effective, but significantly fewer patients experienced side effects while on CBZ. Efficacy of CBZ and PHT was compared in adult patients with partial (n = 10), primary generalized (n = 4), undetermined (n = 4), or secondarily generalized epilepsy (n = 1). Each treatment period lasted 10 weeks, and all medication except PB or PRM was discontinued gradually while CBZ or PHT was increased to a dose of approximately 15 mg/kg for CBZ and 6 mg/kg for PHT; the dose subsequently was adjusted on the basis of plasma levels. No statistically significant differences were found between CBZ and PHT with regard to seizure control (7). Hakkarainen (8) reported a 3-year study of 100 consecutive adults with newly diagnosed epilepsy in which half the patients were randomly allocated to CBZ or to PHT treatment. After the first year, complete control of seizures was achieved in 50 patients (26 on CBZ and 24 on PHT). For nonresponders, the treatment was changed from CBZ to PHT or vice-versa for the second year; complete

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control of seizures was achieved in another eight patients on CBZ and in nine on PHT. For the remaining 33 nonresponders, combined CBZ and PHT treatment was used for the third year, and 5 (15%) of these patients became totally seizure free. New referrals were randomly assigned to receive as initial therapy either CBZ plus placebo or PHT plus placebo, and increases in dosage were made until plasma concentrations were adequate or seizure control was attained. Complete control was achieved in 85% of the 70 who completed the 2-year study, without difference between the two drugs (9). A randomized, double-blind study substituted PHT monotherapy with CBZ or oxcarbazepine in adult outpatients with unsatisfactory seizure control of partial or generalized tonic-clonic seizures (GTCS) or with unwanted side effects; seven (39%) of the patients in CBZ group became seizure free or showed >50% reduction in seizure frequency during the maintenance phase (1 year) compared with the seizure control on PHT therapy (10). In a randomized, double-blind study in young children, CBZ and PHT were equally effective (11).

Carbamazepine versus Phenobarbital

Behavioral and anticonvulsant effects of CBZ versus PB were evaluated in 21 adult patients; after 2 months on the original double-blind prescription, a crossover was made to the other compound for an additional 4-month period. Although no significant difference in efficacy during the final months of each drug treatment phase was found, significant behavioral improvement was noted when on CBZ (12). Children with untreated, newly diagnosed partial seizures received either CBZ (n = 15) or PB (n = 18) for 12 months; if necessary, the dose was gradually increased to the maximum amount tolerated or until the serum level was 10 to 12 mg/L for CBZ and 32 to 40 mg/L for PB. There was a statistically nonsignificant trend toward better seizure control with CBZ (13).

Carbamazepine versus Primidone

Patients with either predominantly psychomotor seizures (n = 31) or GTCS only (n = 14) were initially stabilized on therapeutic doses of PHT and either CBZ or PRM, while all other medications were progressively withdrawn; after 3 months of treatment, their drugs were switched for a second 3-month period. Both drugs had a similar efficacy in partial as well as generalized seizures (14).

Carbamazepine versus Clonazepam

Thirty-six previously untreated patients, 6 to 72 years of age, with newly diagnosed complex partial seizures were randomly allocated to 6-month treatment with either CBZ or clonazepam; 10 of 19 patients on CBZ and 8 of 17 on clonazepam became seizure free (15).

Carbamazepine versus Valproic Acid

In a small study, 25 adult patients (18 untreated, 7 uncontrolled when on PB or PHT) were randomly divided into two treatment groups with VPA (n = 15) or CBZ (n = 10). After 3 months of treatment, any patient who had a seizure while on the first drug was changed to the other drug; no significant difference in seizure control was noted (16). Mattson et al. (17) conducted a multicenter, randomized, double-blind, parallel trial comparing CBZ with VPA in the treatment of 480 adults with complex partial seizures (206 patients) or secondarily GTCS (274 patients). The medication was prescribed initially at dosages adjusted to achieve serum levels in the middle of the therapeutic range. Dosages later were decreased if side effects required change or increased if control was inadequate. Patients were followed 1 to 5 years. For secondarily GTCS, significant differences were not detected between CBZ and VPA, even if a trend favored CBZ. For patients with GTCS only, a retrospective analysis revealed CBZ to be significantly more effective than VPA (18). For complex partial seizures, CBZ was significantly more effective than VPA by a number of outcome measures, but not for total seizure control. In a smaller study, either CBZ or VPA as sole medication was given in 33 previously untreated or insufficiently treated patients, aged 10 to 70 years, who had experienced at least 2 complex partial seizures; complete control during the 24-week maintenance period was achieved in 64% of the patients in both groups (19). The Adult EPITEG Collaborative Group compared CBZ and VPA in adult patients with newly diagnosed partial and secondarily or primarily GTCS. By the end of the 3-year trial period, 80% of the patients available for assessment had achieved 12 months' remission and 60% had achieved 24 months' remission, with a similar proportion in each treatment group (20).

Carbamazepine versus Oxcarbazepine

The Scandinavian Oxcarbazepine Study Group (21) randomly allocated adult patients with previously untreated epilepsy (primarily GTCS or partial seizures with or without secondary generalization) to treatment with either CBZ (n = 82) or oxcarbazepine (n = 83). During the 48-week treatment period, somewhat more patients obtained seizure control (60% versus 52%) or >50% reduction in seizure frequency (81.4% versus 80.2%) with CBZ, a statistically nonsignificant difference.

Carbamazepine versus Vigabatrin

The efficacy and safety of CBZ and vigabatrin (VGB) monotherapy in patients with partial seizures were compared in two randomized, controlled, response-conditional, crossover, open-label trials. In the first trial (22), after 1 year 26 of 50 (52%) patients in the CBZ group and 16 of 50

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(32%) in the VGB group were seizure free. In the second study (23), complete control of seizures was obtained in 20 of 39 (51.3%) patients treated with CBZ, and in 17 of 37 (45.9%) patients treated with VGB, a statistically nonsignificant difference. The combination of the two drugs suppressed the seizures in 5 of 14 resistant cases. Although both agents had a similar efficacy in partial seizures without secondary generalization, CBZ was superior to VGB in patients with secondarily generalized seizures (five of seven and two of six patients treated, respectively).

Carbamazepine versus Lamotrigine

Adults with newly diagnosed, untreated epilepsy were randomized to CBZ (n = 129) or lamotrigine (LTG; n = 131) as sole drugs for a treatment duration of 48 weeks; seizures were partial with or without secondary generalization in 73 patients for each group, and primarily GTCS in 62 patients in the CBZ group and 60 in the LTG group. No difference was found between the two drugs at the time of first seizure or in the proportion of patients remaining seizure free in the last 24 weeks of the trial (38% for CBZ and 39% for LTG); no difference according to seizure type was noted (24). Another trial compared CBZ and LTG as monotherapy in the same category of patients; there was no significant differences between three treatment groups with respect to the number of patients who completed the 24-week treatment seizure free, although the higher LTG dose (200 mg/day) possibly was most effective, with 60.4% seizure-free patients compared with 51.3% (LTG 100 mg/day) and 54.7% (CBZ 600 mg/day) (25).

Carbamazepine versus Phenytoin versus Phenobarbital

Efficacy and tolerance of CBZ were evaluated in a prospective, double-blind study in 45 drug-resistant adult patients; during each of the three 21-day treatment periods, one-third of the patients were assigned to receive PHT (300 mg/day), PB (300 mg/day), or CBZ (1,200 mg/day). CBZ was equal in efficacy to PHT or PB (26). Polymedicated patients with frequent complex partial seizures received CBZ, PHT, or PB in a prospective, double-blind, crossover study; CBZ and PB were more active than PHT, with improvement in 67%, 61%, and 33% of the patients, respectively (27).

Carbamazepine versus Phenytoin versus Valproic Acid

Efficacy of CBZ, PHT, and VPA was compared in 181 new referrals with epilepsy (5 to 69 years of age) over a 14- to 24-month follow-up period (28). One of the three drugs was given initially to all patients on a randomized basis. If the patient failed to respond to the first drug or experienced side effects, a second drug was randomly allocated as single treatment, and, if necessary, a third single drug was prescribed. Patients with GTCS became seizure free in 73% of cases on PHT, 39% on CBZ, and 59% on VPA; a >50% improvement was noted in 8%, 36%, and 19% of cases, respectively. Patients with partial seizures became seizure free in 57% of cases on PHT, 33% on CBZ, and 44% on VPA, and a >50% improvement was noted in 19%, 39%, and 33% of cases, respectively.

Carbamazepine versus Phenytoin versus Phenobarbital versus Primidone

CBZ efficacy was found equivalent to that of PB, PHT, or PRM in 45 mentally subnormal adult inpatients with GTCS (29). In a large, double-blind trial, 622 adult patients were randomly assigned to monotherapy with CBZ, PB, PHT, or PRM and were followed for 2 years or until the drug failed to control seizures or caused unacceptable side effects. Patients had previously been untreated (58%) or undertreated and had simple or complex partial seizures (265 patients) or secondarily GTCS (357 patients) as their predominant seizure type. Overall treatment success was highest with CBZ or PHT, intermediate with PB, and lowest with PRM. Differences in failure rates were explained mostly by the fact that PRM and PB caused more toxic effects. Seizure control was only 39% at 12 months for all patients and all seizure types, and was similar among the drugs tested. CBZ provided significantly better control of partial seizures (30) compared with the barbiturates.

Carbamazepine versus Phenytoin versus Phenobarbital versus Sodium Valproate

In 243 previously untreated adult epileptic patients, no significant differences between the four drugs were found for either measure of efficacy, with 27% remaining seizure free and 75% entering 1 year of remission by 3 years of follow-up (31). Seizure type (partial versus generalized seizures) had no influence on the comparative efficacy.

OTHER STUDIES

CBZ was discovered long before the Good Clinical Practice Guidelines were formulated, and the drug was licensed, at least in Europe, on the basis of open studies that contemporary health authorities considered sufficient for approval. The results of the first administration of CBZ to humans were simultaneously reported by Bonduelle and colleagues and by Lorgé at the Third International Congress of Neuropsychopharmacology (Munich, 1962). The first retrospective or prospective series studies, in which CBZ was prescribed as an add-on medication, date back to the early 1960s.

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Polytherapy

Some of these studies are summarized as examples.

Lorgé added CBZ to the therapeutic regimen of 132 adult patients with different types of epileptic seizures, most of whom had been uncontrolled for many years; the follow-up period ranged from 3 months to 3 years. Twenty-five percent of patients became seizure free and a further 37% had a >50% reduction in seizure frequency; the author concluded that CBZ was an effective antiepileptic agent in all seizure types except absence seizures and was particularly effective in grand mal and psychomotor seizures, and he called attention to its psychotropic effect and its lack of serious side effects (32). Bonduelle et al. prescribed CBZ as add-on therapy in 100 patients of all ages (26 <16 years of age) with PB-resistant seizures. After 1 year, 26 were seizure free, 25 experienced infrequent seizures, and 18 had a >50% reduction in seizure frequency; mood and behavior were considered as improved in almost half the patients (33). Gamstorp (34) gave CBZ to 58 children, 55 of whom had difficult-to-treat partial or generalized seizures. CBZ sometimes was added to the drugs given previously and sometimes replaced one or two of these drugs. Twenty-two patients became seizure free and eight were considerably improved. In three patients, CBZ seemed to increase the number of attacks and cause a deterioration in behavior, with improvement when the drug was stopped. The 24 improved patients remained under observation (35). Of the 19 controlled patients, 13 remained entirely seizure free, 8 for more than 8 years. Of the six patients who relapsed, five had mild and infrequent attacks and only one had a severe relapse 6 months after the initial response. In 1975, Gamstorp (36) reviewed the records of 43 patients with psychomotor epilepsy treated with CBZ at a dose of 20 mg/kg/day. Twenty-three of the 38 children who tried CBZ and tolerated it became seizure free, and 6 were considerably improved. Huf and Schain reported the long-term use of CBZ over a 5-year period; at the time of evaluation, 50 (82%) of 61 children with drug-resistant epilepsy were regarded by their parents as having improved seizure control: 13 were seizure free, and 37 had ≥50% reduction in seizure frequency; no patients were believed to be aggravated (37). Many other studies were conducted with a roughly similar methodology and similar results (38,39).

Some of these studies raised suspicions over the development of tolerance (36). Parsonage reported a retrospective open study of 100 adult patients with refractory complex partial seizures; at the time of review, 11 patients were fully controlled, 22 had a reduction of seizure frequency >50%, 20 had a reduction <50%, 30 were unchanged, and in 15 the seizures showed an increased frequency (however, the drug was withdrawn on this account only in 4 of them) (38). Good control of seizures had been maintained in a number of patients for as long as 12 years, and development of tolerance is not mentionned (38).

Monotherapy

The King's College Hospital group undertook a prospective study of 25 outpatients with GTCS or partial seizures who were treated initially with CBZ and followed for a mean of 1 year. At the end of the period of observation, 21 of 25 (84%) were completely controlled (40). In a prospective study, CBZ was prescribed as a single drug to 11 previously untreated patients and 17 pharmacoresistant patients with either partial or generalized seizures. Ten new referrals and one patient with chronic epilepsy became seizure free, and a >50% reduction in seizure frequency occurred in one new referral and nine refractory patients; the mean follow-up period was 14 months (range, 7 to 32 months) (41). During a 5-year period, CBZ monotherapy was started in 286 patients with various seizure types; CBZ was the drug of first choice in 64%. Of the 253 patients treated for over 3 months at the time of evaluation, 141 were seizure free, and a satisfactory therapeutic effect (no seizure or a reduction in seizure frequency ≥75%) was achieved in a total of 188 patients (74%). In 31 patients (12%), there was an increase in seizure frequency compared with the period immediately before CBZ monotherapy (42). Sixty-eight children with various epilepsy types received CBZ as sole drug for a mean period of 10 months; CBZ was the first therapy in 13 children, whereas in others PB or VPA had been unsuccessful. The seizures disappeared in 43% of cases (43). In another study, polytherapy was replaced by CBZ monotherapy in 43 adult outpatients with chronic epilepsy of various types. Reduction of polytherapy and maintenance of monotherapy was successful in 31 (72%) of the patients; in the monotherapy group, a reduction of >50% in seizure frequency was observed in 25% of the patients with a mean follow-up period of 2 years (44).

Psychotropic Effects of Carbamazepine in Patients with Epilepsy

Reports on psychotropic effects in patients with epilepsy when treated with CBZ have been conflicting, with regard both to their reality and to their mechanisms when their existence was admitted. The first investigators noticed in their patients a frequent and sometimes dramatic improvement in mood and behavior (32,33,45,46). A survey of 40 published reports, concerning approximately 2,500 patients, allowed Dalby (47) to state that a beneficial psychotropic effect was present in 50% of patients. On the other hand, a few studies did not demonstrate any clear-cut change (1,2,29). The question of a psychotropic effect of CBZ treatment therefore was addressed by means of objective neuropsychological testing or rating scales (1,3,12,13,26,48, 49, 50). A review was published in 1985 (51).

Changes observed may be summarized as follows: (a) better alertness, with better attention and concentration;

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(b) better mood, with reduction of depresion and anxiety; and (c) better behavior, with less irritability and aggressivness. Three nonexclusive factors might be responsible for these changes, which could be classified into two separate categories, intellectual and affective functioning, but in reality encompass a broad range of interrelated functions (52):

  1. A direct psychotropic effect of CBZ. Two series of arguments favor a direct action on mood. A correlation between higher levels of CBZ and reduced levels of anxiety and depression was found (49,53). Many investigators have noticed that patients with a past history of emotional or behavioral disturbances were more likely to improve when on CBZ than those without such a history (47). Gamstorp (34) noted that “CBZ did not seem to cause any change in the behavior of patients who had seem mentally normal before the trial.” More direct evidence in support of the psychotropic effects of CBZ derives from its efficacy in patients who have neither seizure disorders nor epileptiform EEG patterns (39,51) (Chapter 26).
  2. A reduction in or control of seizures (26). According to some authorities, this factor may play a role, but is not indispensable. However, one may assume that it is important when CBZ is effective, dramatically reducing the number of seizures and, hence, improving the patient's quality of life (54) and improving cognition, because both epileptic seizures and interictal epileptiform discharges may cause cognitive disturbances and structural brain damage.
  3. Substitution of CBZ for sedative AEDs. The cognitive effects of AEDs have been widely investigated during the past 30 years (55). Double-blind studies compared the behavior and the neuropsychological performances of patients on CBZ or on other drugs. Patients on CBZ were better, but reanalyses of the early studies have shown that the differential cognitive effects of AEDs are subtle (56). These studies do not demonstrate a psychotropic effect of CBZ, but only that, to some extent, CBZ is less neurotoxic than PHT, PB, and PRM. They do not prove that CBZ has no negative effect. Performances were improved after its withdrawal (57,58).

In summary, CBZ has been prescribed as an add-on drug in patients with refractory epilepsy and as one-drug treatment in untreated patients or in previously treated chronic patients, children as well as adults. The overall efficacy results, as measured by control of seizures, ranked CBZ as one of the most effective AEDs. In monotherapy studies, complete control often was achieved, and a reduction of seizure frequency by at least 75% was obtained in 60% to 90% of patients. Reports mainly based on clinical observation suggested additional beneficial psychotropic effects.

MODE OF USE

Indications

Adults

CBZ is effective against the entire range of partial seizures (i.e., simple and complex seizures) with or without secondary generalization (59). In terms of epilepsies and epileptic syndromes, it is a drug of first choice in cryptogenic as well as in symptomatic localization-related epilepsies. CBZ efficacy against GTCS also is well documented. In terms of epileptic syndromes, it can be prescribed in idiopathic generalized epilepsies with GTCS, excepting juvenile myoclonic epilepsy, and in epilepsies without unequivocal generalized or focal seizures.

Children

“Carbamazepine is effective in children when it is administered in the appropriate situation” (60). CBZ is a first-line drug for any patient with partial seizures and secondarily generalized seizures. In terms of epileptic syndromes, its efficiency is documented in cryptogenic and symptomatic localization-related epilepsies, and in idiopathic benign epilepsies of childhood (61). CBZ use in generalized epilepsies is more controversial. Undoubtedly, children with GTCS due to idiopathic epilepsies have been included in some studies, with excellent result. However, there have been reports of children whose seizures were made worse by CBZ (see section on Contraindications).

Dosing Recommendations

CBZ therapy must begin gradually; a full therapeutic dosage may not be achieved for many days or even weeks (59).

Starting Dosage

An evening dosage of 100 mg (half a 200-mg scored tablet) is recommended in adults and children older than 12 years of age; in younger children, a lower dosage is used, depending on the patient's weight (scored chewable tablet or suspension).

Titration Rate

The procedure of rapidly achieving a therapeutic concentration by use of loading doses is not possible with CBZ because of the transient side effects that would occur during initiation of therapy (62). Dizziness, unsteadiness, blurred vision or double vision, sedation, nausea, and vomiting have been noted by early investigators and were well documented in controlled studies in adults, for example

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with a dosage regimen of 400 mg on the first day, 800 mg on the second day, and 1,200 mg on the third day (26). The side effects peaked on the third day. Even if they are mild and transient, they can lead to patients stopping the medication. Furthermore, a rapid titration substantially increases the risk of skin rash and hypersensitivity syndrome. The most convincing report was published in the 1980s (63). Patients undergoing craniotomy for a variety of neurosurgical conditions associated with a high risk of epilepsy received CBZ 200 mg for three oral doses at 8-hour intervals in the 24 hours preceding surgery, and 200 mg three times daily as a maintenance dose thereafter. In 8 of 48 (16.6%) patients, exanthematous skin eruptions developed, a much higher incidence than usual. Therefore, the initial dosage must be increased slowly to the full therapeutic dosage over a variable period. When the clinical situation allows it, a weekly interval is preferred (59). In case of frequent seizures, the interval should be shorter (e.g., every second day), with a slower increase if side effects appear. In general, dosage is increased until seizures cease or dose-related side effects occur. In case of side effects, the total daily dose is reduced by 100 or 200 mg.

Initial Target Maintenance Dosage

Because both low doses and low plasma concentrations may give complete seizure control in many patients, at least in patients with newly diagnosed epilepsy, it is important not to hurry and to make individual adjustments based on clinical grounds. Patients with newly diagnosed epilepsy were controlled with a mean CBZ dose of 7.5 mg/day, whereas patients with chronic epilepsy were controlled only with a mean CBZ dose of 10.3 mg/kg (64). In general, there is little correlation between dosage and therapeutic efficacy (26,62,64,65). Doses giving control ranged from 600 to 1,600 mg in adults (38) (i.e., 3 to 15.9 mg/kg) (64).

CBZ induces its own metabolism during prolonged administration, which results in increased clearance (Chapter 21). Thus, sequential increases in dosage may be necessary over the first few weeks of treatment (9).

Optimal Range of Maintenance Dosages

The mean effective dosage is probably 20 mg/kg in children younger than 5 years of age and 10 mg/kg in other patients. However, there is no one dosage of CBZ appropriate for all patients.

Three reasons may explain persisting seizures: poor compliance, an inadequate dosing regimen, and a truly CBZ-resistant epilepsy. Plasma level determinations allow easy detection of poorly compliant patients. Because of a poor correlation between dosage and efficacy, it was recommended that CBZ dosage be adjusted by plasma level monitoring. It was assumed that the serum CBZ level was positively correlated with the degree of seizure control (66). Optimum seizure control was reported to occur with CBZ plasma concentration in the range of 5 to 10 mg/L (67). Other authorities stated that such a wide range of serum levels was associated with seizure control that it was not possible to define a therapeutic range for CBZ (41,64). The relation of plasma levels to drug efficacy and toxicity is inexact. When large groups of patients are considered, it is not uncommon to find that uncontrolled patients have higher plasma levels than controlled patients. Plasma level monitoring is a useful tool for the clinician, but has no definitive value. In uncontrolled patients, it is necessary to push the drug to the maximum clinically tolerated dose, regardless of its plasma level.

Dosage Intervals

The plasma concentration of carbamazepine is characterized by rapid absorbtion and a relatively short elimination half-life, which may lead to considerable fluctuation of the level between doses. Interdosage fluctuations in CBZ plasma concentrations with high peak levels are considered to be responsible for transient side effects occurring 2 to 4 hours after drug intake (i.e., peak-related side effects) (68, 69, 70). In patients receiving comedication with enzyme inducers, such as PHT, PB, and PRM, the CBZ elimination half-life is rather short, ranging from 5.6 to 16 hours (mean, 8.2 hours). For these reasons, some epileptologists concluded that CBZ should be administered no fewer than four or five times a day. Such frequent dosing would be very uncomfortable for most outpatients and would lead to poor compliance. Even a thrice-daily administration, as recommended (71), probably is unnecessary for many patients. Two or three doses provide approximately the same amount of CBZ available in circulation, with a mean fluctuation of 57% ± 20% and 56% ± 29%, respectively (72). A twice-a-day schedule would be as effective (6,59). However, when high doses of CBZ are necessary, acute toxicity could be avoided by splitting the dosage into a thrice-daily pattern.

Extended-Release Carbamazepine

Because detrimental consequences might result from large plasma drug level fluctuations, with either breakthrough seizures at the trough level times or intermittent peak-related side effects, new CBZ formulations were developed in the late 1980s. They have prolonged absorption (slow-release, extended-release, controlled-release) characteristics (CBZ-CR). They give higher minimum serum levels (Cmin) and lower maximum serum levels (Cmax). In adults, the mean daily fluctuation was 30% ± 10% with CBZ-CR twice-daily administration, whereas it was 61% ± 17% with CBZ thrice daily (72). In children, the interdose variation

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in CBZ plasma concentration was 21% for the patients receiving CBZ-CR and 41% for the patients receiving comparable doses of the standard CBZ preparation (73). A once-daily evening dose of CBZ-CR was considered to give therapeutically efficient 24-hour levels (74). In a multicenter, double-blind, crossover trial of CBZ versus CBZ-CR in 30 patients, fluctuations of CBZ and CBZ-epoxide levels at steady state were significantly lower for CBZ-CR, leading to a significant decrease in intermittent side effects (75). In adult patients, fewer cognitive side effects of CBZ were observed when fluctuations in the serum concentration were smoothed by slow-release absorption (76). More recently, a randomized, double-blind, two-way, crossover study compared the pharmacokinetics of twice-daily CBZ-CR and four-times-daily immediate-release CBZ in 24 adult patients with epilepsy. No differences were found for area under the curve, Cmax, and Cmin (77). Patients who had been on high-dosage conventional CBZ reported significant reductions in side effects with CBZ-CR, and several patients were noted to have improved seizure control because higher doses were possible with fewer side effects (78). Similar advantages occur with use of other delayed-release formulations (Tegretol XR and Carbatrol).

Generics

Controversy over generic drugs has existed for decades, and therapeutic equivalence and bioequivalence are issues with generic drugs (79). A variety of case reports and uncontrolled studies reported differences between generic and brand products, and among generics. These differences could result in loss of seizure control or in development of toxic effects. Such a loss of control in patients switched from Tegretol to a generic CBZ product, with subsequent recovery of control on switching back to Tegretol, was reported (80).

Current Role in Epilepsy Management

Monotherapy is the rule in untreated patients (81), and may be possible in certain patients previously treated with unsatisfactory results, but not in all of them (82). The advantages of a single-drug treatment are well established (83). CBZ currently is the most frequently prescribed first-line drug for the treatment of partial tonic-clonic seizures and GTCS in both adults and children. Conversely, it is ineffective against some particular types of generalized seizures (see later). Patients remaining uncontrolled at the maximum tolerable dose of CBZ should be given another treatment, which may be alternative monotherapy. However, certain patients whose seizures are not controlled with a single drug benefit from drug combination (84). After failure of monotherapies, bitherapies must be considered, despite pharmacokinetic and pharmacodynamic problems of interactions, because of solutions to these problems (85,86). Several reports are in favor of the efficacy of bitherapy in the 20% to 30% of patients who are not controlled with one drug only. Addition of VPA in 100 CBZ-resistant patients resulted in 17% seizure free, and improvement was noted in 39% (87). Confirmation was given in a smaller study (88). The aim of a randomized, double-blind study in patients with partial seizures uncontrolled on CBZ monotherapy was to see how many did better on bitherapy (89). Approximately 10% of the 215 adult patients remained seizure free during the final 3-month treatment period. This study suggests that when a Na+ blocking agent, such as CBZ, fails, adding a γ-aminobutyric acid agonistdrug, such as VPA or VGB, may be successful. However, some drug-resistant patients do benefit from PHT/CBZ combination therapy without a significant increase in drug toxicity (8,90).

CBZ withdrawal, for failure as well as for success, always should be progressive to prevent withdrawal seizures.

Use in Special Populations

Infants and Children

Because children metabolize CBZ faster than adults, larger doses can be recommended in children (60). The younger the patient, the higher the CBZ clearance rate, and hence the higher the dosage required. This statement is true mainly for infants (91). However, even in children, twice-daily administration is feasible (36,43,92).

Women of Childbearing Potential

CBZ decreases the efficacy of contraceptive pills by induction of cytochrome P450 isoenzyme 3A (CYP3A)-mediated metabolism of oral contraceptive corticosteroids (Chapter 22). Epidemiologic data suggest that there may be an association between the use of CBZ during pregnancy and fetal malformations (93). Breast-feeding usually is not contraindicated (94).

The Elderly

No systematic studies in geriatric patients have been conducted, but in daily practice as well as in clinical studies, elderly patients were prescribed CBZ without harm. Nonspecific problems include (a) a possible increased sensitivity to the effects of medication owing to age-dependent changes in pharmacokinetics and pharmacodynamics; and (b) frequent comedication, with risks of meaninful drug interactions (Chapters 13 and 22).

Comedicated Patients

Patients being treated for epilepsy can be at risk when they are prescribed other drugs for concomitant diseases (95) because of drug-drug interactions (Chapter 22). Clinically,

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CBZ metabolism induction by other drugs is less important than its inhibition by CYP3A4 inhibitors. Toxic symptoms and signs may develop in the patient in a few days. The combination of CBZ and VPA must be prescribed with caution. By inhibiting epoxide hydrolase, VPA increases CBZ-epoxide levels (96). This may result in side effects. Another inconvenience of an increase in CBZ-epoxide is the increase in formation of arene oxides with probable teratogenicity, which means that the combination of CBZ and VPA must be avoided in pregnancy. The combination also must be avoided in infants because CBZ increases the formation of delta-4 VPA, a probably hepatotoxic metabolite (97).

Precautions

CBZ should be prescribed with caution in patients with a history of cardiac, hepatic, or renal damage and adverse hematologic reactions to other drugs.

CBZ adverse effects are discussed fully in Chapter 26. In patient management, the skin, the central nervous system, and the blood must be checked for evidence of toxicity. Rashes occur in approximately 5% to 10% of patients. They appear in most cases within the first few months after initiation of therapy. They usually are transient, but can precede a Stevens-Johnson syndrome. Our personal policy is to stop the therapy. It is important to determine if neurotoxicity is peak dependent or dose dependent. When it is peak dependent, subdividing the daily dosage is sufficient. When it is dose dependent, the daily dosage must be decreased. A wide range of serum levels was associated with these side effects (28). However, concentrations greater than 12 mg/L usually have been associated with toxic signs (2,66).

Because of very rare aplastic anemias and rather common benign leukopenias, hematologic monitoring has been recommended. It no longer is requested by many European neurologists (42). Porter (59) suggested checking the white blood cell count weekly for 1 month and biweekly for 6 additional weeks after initiation of therapy.

Routine laboratory monitoring may be helpful for early detection of chronic adverse reactions, but severe adverse reactions can occur despite careful surveillance (98).

Contraindications

CBZ should not be used in patients with known sensitivity to any of the tricyclic antidepressants, and its use with monoamine oxidase inhibitors is not recommended.

In the 1990s, there was a growing awareness that AEDs can worsen epileptic conditions by aggravating preexisting seizures or by triggering new seizure types (99,100). To date, exacerbation of seizures and worsening of electroencephalographic (EEG) recordings by CBZ has been reported in a number of case reports, and there is accumulating evidence that CBZ is relatively contraindicated in certain types of seizures and specific epilepsy syndromes. An increase of GTCS and absences and precipitation of atonic and myoclonic seizures in children have been reported (101, 102, 103, 104, 105, 106, 107). It has been well known since the early 1970s that CBZ is not indicated in the treatment of typical absence seizures. Nonetheless, of 18 consecutive referrals of children with resistant typical absences only, 8 were erroneously treated with CBZ either as sole drug or as an add-on. Frequency of absence seizures increased in four children, and in two of these myoclonic jerks developed that resolved on withdrawal of CBZ (108). CBZ-related aggravation is not limited to children. In adult patients, CBZ therapy resulted in exacerbation or de novo appearance of absence or myoclonic seizures (109, 110, 111, 112, 113).

In summary, exacerbation of seizures can result from CBZ therapy. At particularly high risk are children with symptomatic or cryptogenic generalized or multifocal severe epilepsy, characterized by mixed seizure types, and generalized, synchronous, spike-wave discharges. Patients with any of the idiopathic epilepsies also are at risk for CBZ-associated seizures, whatever their age, particularly when they experience absence seizures or myoclonic jerks. An EEG might help screen higher-risk patients, and serial EEGs are recommended when starting CBZ therapy in patients at risk: Seizure exacerbation almost invariably is accompanied by the development of generalized epileptiform discharges.

SUMMARY

Many studies have demonstrated CBZ efficacy against cryptogenic and symptomatic localization-related epilepies, undetermined epilepsies, and some seizure types in a number of forms of idiopathic generalized epilepsies. Its efficacy in symptomatic generalized epilepsy is controversial, and it may worsen absence and myoclonic seizures. It is effective as single-drug treatment and in combination therapy. However, monotherapy always is preferable. In previously untreated patients, a moderate dosage often is sufficient. In seizures that are difficult to control, CBZ must be pushed to the maximally tolerated dose. Plasma level monitoring is more useful in polytherapy than in monotherapy. Dose choice is determined on a clinical and not a laboratory basis. CBZ was shown to be as effective as other AEDs, with less long-term side effects than PB, PRM, or PHT. It is a drug of choice because of either a direct psychotropic effect or indirect beneficial effects resulting from a lack of neurotoxicity.

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