INTRODUCTION

Carbamazepine is one of the most frequently used antiepileptic medications, and is arguably supported by the best evidence base (1). It is highly effective for treatment of epilepsy with partial and generalized tonic–clonic seizures. Carbamazepine also has been reported to benefit neuropathic pain and certain affective disorders. The major disadvantages have been its propensity to interact with other drugs, to cause rashes, and to aggravate absence, myoclonic, and astatic seizures in patients with generalized epilepsy. These disadvantages, coupled with the robust efficacy, led to the search for other dibenzazepine compounds.

Oxcarbazepine is a 10-keto analog of carbamazepine. Compared to carbamazepine, it has reduced capacity for induction of hepatic cytochrome drug-metabolizing enzymes resulting in fewer drug interactions and also decreased risk of rash (2,3). Eslicarbazepine is a third-generation novel antiepileptic drug that belongs to the dibenzazepine family. It has a longer half-life, linear pharmacokinetics, and low potential for drug interactions, offering an alternative to the other dibenzazepines (4).

STRUCTURE AND CHEMISTRY

All three drugs belong to the dibenzazepine family and are structurally similar to tricyclic antidepressants. They all share a dibenzazepine nucleus but differ in their carbamoyl side chains (Figure 51.1), which confers their difference in pharmacokinetics and side effect profile (5). Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon-carbon double bond on the dibenzazepine nucleus at the 10th position. Eslicarbazepine has a 5-carboxamide substitute at the 10,11 position.

MECHANISM OF ACTION

Carbamazepine, oxcarbazepine, and eslicarbazepine have a similar mechanism of action. They work by blocking the voltage-gated sodium channel, which plays an essential role in the generation and propagation of epileptic discharges. In vitro studies demonstrate that both carbamazepine and eslicarbazepine competitively interact with the neurotoxin site 2 of the voltage-gated sodium channel, with a higher affinity for the inactivated state than the resting state (6,7). In the maximal electroshock and amygdala kindling models in rodents, the potency of eslicarbazepine was similar to carbamazepine and higher than that of oxcarbazepine (8). Eslicarbazepine’s affinity for the inactivated state of the voltage-gated sodium channel is similar, while affinity for the resting state is three times lower compared to carbamazepine and suggests enhanced inhibiting selectivity of eslicarbazepine for rapidly firing neurons, which, in turn, may lead to decreased adverse effects (6). We will discuss in detail the pharmacokinetics, drug interactions, clinical efficacy, and side effects of all three dibenzazepine compounds (Table 51.1).

CARBAMAZEPINE

Pharmacokinetics

Absorption

The bioavailability of carbamazepine has been estimated to be 75% to 85% (12,13). Food variably increases the rate of absorption (12). Studies have shown that oral absorption of carbamazepine is about 70% of intravenous formulation (14,15). The bioavailability in a suspension, tablet, and extended release tablet is similar; however, suspension is absorbed faster, whereas the extended release is slightly slower than the conventional tablet (9). Extended release formulations produce significantly lower fluctuations in serum levels, leading to lower adverse effects compared to immediate release formulations (16). The branded extended release formulations Carbatrol and Tegretol XR use different technologies. Carbatrol is formulated using Microtrol technology and is composed of immediate, enteric, and extended release beads within a capsule. The capsule can be swallowed whole or can be opened and sprinkled on food (17). Tegretol XR is formulated using OROS technology, which depends on gastric absorption of osmotically drawn water, forcing carbamazepine out of the tablet with hydrostatic pressure (18). In some patients, extended release formulation allows twice daily dosing, which is more convenient, encourages compliance, and reduces side effects (19). An intravenous formulation of carbamazepine solubilized in cyclodextrin matrix has been developed by Lundbeck and may soon become available (14).

FIGURE 51.1 Structures of dibenzazepine antiepileptic drugs.

Source: From Oztiryaki AH, Soares-da-Silva P. Therapeutic drug monitoring of the newer anti-epilepsy medications. Pharmaceuticals. 2010;3(12):3629–3632.

TABLE 51.1

Distribution

The volume of distribution for carbamazepine varies from 0.93 to 1.28 L/KG (20). The brain-to-plasma ratio of both carbamazepine and carbamazepine epoxide is approximately 1, with a range of 0.8 to 1.6 (20,21). Approximately 75% and 50% of carbamazepine and carbamazepine epoxide (CBZE) are bound to albumin, respectively (20). Carbamazepine is a lipophilic compound that crosses the placenta and penetrates breast milk. Among mothers taking carbamazepine, concentrations in their breast milk are so low that nursing infants rarely ingest a substantial amount.

Metabolism

Carbamazepine is eliminated largely by hepatic metabolism. The predominant elimination pathway in humans involves oxidation to carbamazepine-10-11 epoxide, which has actions similar to the parent drug but is less potent (22). Cytochrome P450 3A4 has been identified as the major enzyme isoform responsible for this oxidation process. The epoxide is hydrolyzed subsequently to form an inactive 10,11 dihydroxide, the principal urinary metabolite. Lesser amounts of carbamazepine are metabolized by aromatic hydroxylation and also direct N-glucuronidation (23). Carbamazepine has linear, predictable elimination kinetics (24,25). Carbamazepine induces its own metabolism by stimulating the activity of the CYP 3A4 iso-enzyme of cytochrome P450, a process called autoinduction (26,27). Among both children and adults, who have not previously taken hepatic enzyme-inducing drugs, the half-life of carbamazepine decreases approximately 50% as autoinduction takes place, with the half-life declining from 36 hours after the first dose to 18 to 20 hours following chronic monotherapy in adults (12,27). Likewise, studies in children indicate similar magnitudes of change with doubling of carbamazepine clearance after 2 to 3 weeks of therapy (28). Thus, in all age groups, autoinduction causes levels to be approximately 50% of what would be predicted from the first dose pharmacokinetics. Auto-induction is usually complete 3 to 6 weeks after this medication is begun, then the pharmacokinetics become linear. In patients who are already on drugs that cause CYP3A4 iso-enzyme stimulation, autoinduction may not be a significant issue.

Carbamazepine elimination is influenced by age, pregnancy, and drug interactions (29). As with other antiepileptic drugs, the relative clearance of carbamazepine is much higher in young children compared to adults. Younger patients and pregnant women in their last trimester have higher clearance and require relatively higher doses than other patients (24).

Drug Interactions

Carbamazepine has the potential for multiple drug interactions and caution should be used in combining it with other drugs, including other antiepileptic drugs. It is sensitive to interaction with a large number of agents that induce or inhibit CYP3A4 isozymes. As this pathway metabolizes many medications, it is prudent to look up any interaction before adding a new drug. Numerous drugs, including phenytoin, phenobarbital, and primidone, induce hepatic enzymes, resulting in decreases in carbamazepine levels (30). Carbamazepine as a strong CYP450 inducer reduces concentration of several drugs including other antiepileptic drugs that are metabolized by the liver (31). It decreases the levels of valproic acid, phenytoin, ethosuximide, lamotrigine, topiramate, zonisamide, perampanel, ezogabine, and benzodiazepines. Carbamazepine also increases the metabolism of hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies (32).

When adding or deleting carbamazepine, remember that other inducers of hepatic cytochrome P450 enzyme enhance carbamazepine metabolism and vice versa. Thus, when carbamazepine is added to an antiepileptic drug regimen, it usually lowers the concentration of other antiepileptic drugs that are subject to hepatic biotransformation. For this reason, the dose of the first drug should be held constant as carbamazepine is added until the concentration of the carbamazepine exceeds 4 μg/L; the original drug can then be tapered over a period of 3 or more weeks, depending on the drug. After this is completed, the carbamazepine level usually increases if the drug that was replaced was a cytochrome P450 inducer.

Several drugs inhibit carbamazepine metabolism and increase its levels, potentially leading to toxicity (Table 51.2). These medications include erythromycin, cimetidine, propoxyphene, and isoniazid. Chronic grapefruit juice raises the bioavailability of carbamazepine by inhibiting CYP3A4 enzymes (33). Valproate increases the unbound fraction of both carbamazepine and carbamazepine epoxide; it also it inhibits hydrolysis of carbamazepine epoxide, thereby increasing its concentration and adverse effects.

Evidence has also been found for a pharmacodynamic interaction between carbamazepine and phenytoin in experimental animals (34) and between carbamazepine and lamotrigine in humans (35). There was more likelihood of neurotoxicity when carbamazepine combined with these drugs or with the other dibenzazepines.

Clinical Efficacy

Carbamazepine is effective in controlling partial and generalized tonic–clonic seizures (37,38). Rarely, it has been reported to worsen a variety of seizures, most notably absence, atonic, and myoclonic seizures in patients with generalized epilepsies characterized by diffuse bilaterally synchronous spike-and-wave discharges on electroencephalogram (39,40).

TABLE 51.2

*Interaction is variable. Usually carbamazepine decreases phenytoin levels, but sometimes the opposite is seen.

Source: Adapted from Refs. (9,36).

Numerous studies have shown that carbamazepine is as effective as phenytoin, phenobarbital, and valproic acid in patients with partial epilepsy but better tolerated than phenobarbital (41–50). Studies comparing leviracetam and carbamazepine in both children and adults showed similar efficacy and tolerability when extended release formulations of carbamazepine are used (51,52). Carbamazepine was found to be as effective as lamotrigine in a study involving both children and adults, but lamotrigine was slightly better tolerated (53). Double-blind comparison of topiramate, valproic acid, and carbamazepine monotherapy in children showed no difference in efficacy measures among these drugs (54). The Canadian study group for childhood epilepsy showed that carbamazepine is as effective as clobazam and phenytoin in new-onset partial epilepsy (55). Carbamazepine was found to be more effective than gabapentin and vigabatrin in comparison trials (56,57).

Carbamazepine in therapeutic concentration has few effects on the electroencephalogram. High levels of carbamazepine can produce generalized slowing. The effect of carbamazepine on spikes and sharp waves depends on its efficacy in the individual patients. When carbamazepine is effective in preventing partial seizures, focal spikes at first become briefer and sharper and eventually may disappear (58). Discontinuation of carbamazepine is associated with an increase in mean dominant background rhythm frequency (59). Generalized spike-and-wave abnormalities are either unaffected or worsen (60).

Other uses of carbamazepine include treatment of chronic neurogenic pain (61,62), hemifacial spasm (63), paroxysmal kinesigenic dyskinesia (64), and affective disorders (65–70).

Adverse Effects

Carbamazepine is generally well tolerated (71–73). Most of the side effects are mild; in one study, only 3% required discontinuation of medication and another 3% required dosage reduction (73). Gastrointestinal complaints are uncommon.

The most common side effects are sedation, dizziness, incoordination, ataxia, and double vision, and are mostly transient and dose-related (74). Brief episodes of toxicity can result from transient elevation of carbamazepine levels due to fluctuation between doses (19,75–77). In these situations, extended release formulation appears to be better tolerated. As with many antiepileptic drugs, starting at a low dose and slowly escalating to the desired maintenance dose causes fewer side effects (75). With chronic therapy, tolerance develops to the neurologic side effects and may abate completely (70). Patients with cerebellar atrophy have a decreased threshold for developing dizziness and ataxia with carbamazepine (78). Idiosyncratic neurologic adverse reactions like acute behavioral changes, tics, and dystonia are rare (79–81).

Carbamazepine is associated with dose-dependent reduction in neutrophil counts in 10% to 20% of patients. In one study, leukopenia (WBC <4,000 per mm³) was seen in 17% of patients less than 12 years old and 8% of children aged 12 to 17 years (82). These changes sometimes persist but usually do not forebode serious problems (43). Rarely does the neutrophil count fall below 1,200/mm³ (83). For this reason, routine screening has been questioned. The incidence of severe hematologic toxicity such as aplastic anemia, agranulocytosis, and thrombocytopenia is rare and estimated to be less than 1 per 50,000 (84–89).

Hyponatremia caused by carbamazepine occurs in patients of all ages (90) but is more common among the elderly (91,92). It is usually mild and asymptomatic in children (93). Carbamazepine monotherapy appears to decrease bone mineral density and increase the risk of fractures, but polytherapy is associated with a larger decrease in bone mineral density (94). Many authors recommend vitamin D and calcium supplementation to prevent this complication. Carbamazepine also lowers the plasma concentration of thyroid-binding globulin and T3 and T4 levels, but clinical hypothyroidism is rare (95). Carbamazepine does have teratogenic side effects and the rate of major congenital malformations, especially neural tube defects, may be at least two-fold higher than expected with in utero exposure. It is classified by the Food and Drug Administration (FDA) as category “D” (96). Though the overall risk for major congenital malformation is low, still many recommend periconceptual folate supplementation in spite of uncertain efficacy. There is emerging evidence of alteration of markers of vascular risk by long-term monotherapy with carbamazepine that might enhance the risk of atherosclerosis (97).

Hypersensitivity to carbamazepine, especially allergic rash, is common; the incidence varies from 4% to 10% in various series (48,98). Rarely, severe skin reactions like erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis occur. Patients carrying Human Leukocyte Antigen allele, HLA-B* 1502, are at strongly increased risk of carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (99). This HLA allele has been reported almost exclusively in patients of Asian origin; a recent FDA alert recommends screening for this allele among at-risk populations before starting carbamazepine (100). Hypersensivity reactions characterized by fever, rash, renal, and hepatic toxicity are very rare (88,101–103). Other rare idiosyncratic reactions include systemic lupus erythematous and pseudolymphoma (104–107).

Monotherapy

Monotherapy with carbamazepine is one of the treatments of choice for partial and generalized tonic–clonic seizures. Treatment with carbamazepine should be initiated at 5 to10 mg/kg/day and increased in 5 to 10 mg/kg/day weekly increments until the seizures are controlled or intolerable side effects appear. The usual maintenance doses are 10 to 35 mg/kg/day (9). In children weighing more than 40 kilograms, adult doses should be used. Children, especially those younger than 5 years of age, metabolize carbamazepine faster than adults and may need relatively higher doses. The immediate release formulations are dosed three times a day, while the extended release formulations may be given twice daily. Monotherapy is superior to polytherapy, considering frequent drug interactions with other antiepileptic medications (108,109).

OXCARBAZEPINE

Oxcarbazepine (OXC; Trileptal) is the 10-keto analog of carbamazepine. It has gained wide acceptance and use for treatment of epilepsy with partial onset seizures (110–112). The main advantage of oxcarbazepine over carbamazepine is its relatively reduced capacity for induction of hepatic cytochrome drug-metabolizing enzymes, resulting in fewer drug interactions and reduced risk of allergic rash (2,3). Oxcarbazepine and carbamazepine appear to share the same mechanisms of action and act to limit high-frequency firing by acting on voltage-dependent sodium channels (113).

Pharmacokinetics

Oxcarbazepine is well absorbed after oral administration and then it is rapidly converted by cytosolic arylketone reductase to the active 10-monohydroxy derivative (MHD), which is responsible for most of the antiepileptic effect (114). Concentrations of MHD peak 4 to 12 hours following oral doses of oxcarbazepine (115). Concentrations of both compounds are linearly related to dose and have been reported to be little affected by hepatic enzyme-inducing agents (115). Neither compound is highly protein bound, with oxcarbazepine being 60% bound and MHD 40% bound (116). Whereas the half-life of oxcarbazepine is 1 to 2.5 hours, the half-life of MHD is 8 to 10 hours in children (117,118) with longer values reported in normal volunteers, adults, and elderly patients (115,117,118). Moreover, as with other antiepileptic drugs, younger children eliminate oxcarbazepine and MHD faster than older children and adults, with young children (age 2–5 years) having half-lives for MHD that were 30% shorter than those found in older children (age 6–12 years) (119,120). Recently, extended release formulation of oxcarbazepine has been made available, which can be given once daily. Although the conversion of oxcarbazepine to MDH results in a racemic mixture of enantiomers with the dextrorotatory isomer being produced in five-fold greater amounts than the levorotary isomer (121,122), both stereoisomers are active antiepileptic agents. The MHD is eliminated mainly in urine after conjugation to glucuronic acid. Mild to moderate hepatic dysfunction has no effect on oxcarbazepine and MHD elimination, but renal impairment can necessitate reducing the dose (115). Both oxcarbazepine and MHD cross the placenta and also enter breast milk in concentrations roughly half of those in plasma (123,124). Clearance of oxcarbazepine and MHD increases during pregnancy, causing levels to decrease.

Oxcarbazepine Drug Interactions

Unlike carbamazepine, oxcarbazepine does not induce its own metabolism and autoinduction is not an issue. Oxcarbazepine inhibits CYP2C19 and, although usually clinically irrelevant, it can increase phenytoin concentrations when phenytoin levels are at the upper end of the therapeutic range (Table 51.3). Both oxcarbazepine and MHD can induce UDP-glucuronyl transferase activity. Oxcarbazepine usually has little or no effect on the concentrations of valproate, phenobarbital, or carbamazepine,; however, each of these compounds can decrease the concentration of MHD by 20% to 40% (10). Interactions with lamotrigine have been reported to be negligible (125), but it is known to reduce the concentration of perampanel. Oxcarbazepine also induces CYP3A4/5, whereby it can lead to a dose-dependent reduction in the concentration and effectiveness of low estrogen dose oral contraceptives (126,127).

Clinical Efficacy

Both oxcarbazepine and its metabolite have a spectrum of activity that is similar to carbamazepine. Oxcarbazepine is effective as add-on therapy in refractory seizures and as initial monotherapy in new-onset partial seizures (128). Although oxcarbazepine and carbamazepine seem to share common mechanisms of action, some patients who are inadequately treated with carbamazepine improved after they were switched to oxcarbazepine (129). In a double-blind, randomized study that compared oxcarbazepine to phenytoin in 193 children aged 5 to 18 years with new-onset partial or generalized tonic–clonic seizures, efficacy was equivalent, with approximately 60% of subjects in each group becoming seizure-free (130). However, oxcarbazepine was better tolerated, as demonstrated by more subjects discontinuing phenytoin due to adverse effects. Oxcarbazepine is usually started at 8 to 10 mg/kg/day given as a twice-a-day regimen and increased by 10 mg/kg/day at weekly intervals to the desired maintenance doses of 20 to 50 mg/kg/day. In adults, it can be started as 300 mg twice daily and increased by 300 mg every 3 days up to 1,200 to 2,400 mg/day depending on the response. The extended release formulation should be started at 600 mg per day in adults and increased weekly by 600 mg to achieve the recommended daily dose of 1200 to 2400 mg.

Adverse Effects

Studies of cognitive adverse effects of carbamazepine and oxcarbazepine have found no differences (131). Like carbamazepine, oxcarbazepine has been reported to exacerbate seizures in patients with generalized epilepsy, including some patients with benign partial epilepsy of childhood (41,132–134). Oxcarbazepine has a lower incidence of allergic reactions and is less neurotoxic (135–138). However, it causes symptomatic hyponatremia more frequently than carbamazepine (136–139), with hyponatremia (<125 mEq/L) occurring in 3% of subjects in initial clinical trials (139). Patients taking other medications for example, diuretics that can lead to decreased serum sodium levels are more likely to develop oxcarbazepine-induced hyponatremia, and should be monitored regularly. Neurologic side effects are the most common and include dizziness, headache, diplopia, ataxia, fatigue, and somnolence; these are followed by gastrointestinal side effects, such as nausea and vomiting (140–143). Rashes reported with oxcarbazepine include Stevens-Johnson syndrome and toxic epidermal necrolysis in addition to milder maculopapular eruptions (125). Among patients who have had prior allergic reactions to carbamazepine, the risk of allergic cross-reactivity with oxcarbazepine is 25% (125). Therefore, patients with a prior serious rash to carbamazepine should avoid treatment with oxcarbazepine and eslicarbazepine. Patients carrying the HLA-B*1502 allele may be at increased risk for Stevens–Johnson syndrome/toxic epidermal necrolysis with oxcarbazepine treatment and it’s use should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks (10). As with patients taking carbamazepine monotherapy, those taking oxcarbazepine monotherapy also are prone to have reduced concentrations of 25-OH vitamin D, which if untreated heightens the risk of osteopenia (144).

TABLE 51.3

Source: From Ref. (10). Novartis. Trileptal prescribing information. Retrieved from http://www.pharma.us.novartis.com/product/pi/pdf/trileptal.pdf.

ESLICARBAZEPINE

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