Carbamazepine and Oxcarbazepine
Carlos A. M. Guerreiro
Marilisa M. Guerreiro
Carbamazepine (CBZ) is one of the most often prescribed drugs worldwide for the treatment of neurologic disorders. It has been used in patients with epilepsy, chronic pain syndromes, and a variety of psychiatric disorders since the early 1960s (1, 2, 3). CBZ is considered an efficacious agent for the treatment of partial and secondarily generalized seizures in children and adults, with an excellent side effect profile (4, 5, 6, 7, 8).
Oxcarbazepine (OXC), the 10-keto analogue of CBZ, has been used largely as an alternative for CBZ because of its more favorable pharmacologic and adverse event profiles.
CHEMISTRY AND MECHANISM OF ACTION OF CARBAMAZEPINE AND OXCARBAZEPINE
CBZ is an iminodibenzyl derivative. Both CBZ and OXC are tricyclic anticonvulsant agents that are structurally similar to antidepressants. However, unlike the tricyclic antidepressants, CBZ and OXC are neutral substances because of their carbamoyl side chains (Fig. 53.1).
OXC as a prodrug is rapidly and completely metabolized to the monohydroxy derivative (MHD). CBZ and OXC (and also their active metabolites—CBZ epoxide and MHD) share many known actions of antiepileptic drugs (AEDs). They produce blockade of voltage-dependent ionic membrane conductance (especially sodium, potassium, and calcium), resulting in stabilization of hyperexcited neural membranes and synaptic actions of such neurotransmitters as γ-aminobutyric acid (GABA), glutamate, purine, monoamine, N-methyl-D-aspartate and acetylcholine receptors; the effect is diminution of propagation of synaptic impulses (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). There are subtle differences in the mechanisms of action of CBZ and OXC. For instance, MHD blocks N-type calcium channels, whereas CBZ blocks L-type (19,20).
CARBAMAZEPINE
Absorption and Distribution
CBZ is absorbed from the gastrointestinal tract slowly, with an estimated bioavailability of about 80% to 90% (23). The bioavailability of the agent is similar for all formulations—that is, tablets, solution, oral suspension, chewable tablets, and extended-release tablets/capsules (24, 25, 26, 27). However, some studies have demonstrated the advantages in reducing serum level fluctuation with controlled-release forms of CBZ (27, 28, 29). Peak plasma concentration with chronic dosing is 3 to 4 hours (30). CBZ is a lipophilic compound that crosses the blood-brain barrier readily and is rapidly distributed to various organs, including fetal tissues and amniotic fluid as well as breast milk (31, 32, 33, 34, 35). Pharmacokinetic parameters are shown in Table 53.1 (31,36, 37, 38, 39, 40, 41). Definitions and concepts of these parameters are discussed in Chapter 45.
Metabolism
CBZ clearance is accomplished almost entirely via hepatic metabolism. The major pathways of CBZ biotransformation, consecutively or as parallel reactions, are the epoxidediol pathway, aromatic hydroxylation, and conjugation. Metabolites from these major routes account for 80% to 90% of total urinary radioactivity. Forty percent of the main metabolites found in urine are a result of oxidation of the 10,11 double bond of the azepine rings, 25% are a
result of hydroxylation of the six-membered aromatic rings, 15% are a result of direct N-glucuronidation at the carbamoyl side chain, and 5% are a result of substitution of the six-membered rings with sulfur-containing groups (42).
result of hydroxylation of the six-membered aromatic rings, 15% are a result of direct N-glucuronidation at the carbamoyl side chain, and 5% are a result of substitution of the six-membered rings with sulfur-containing groups (42).
 Figure 53.1 Chemical structure and main first-step metabolic pathways of oxcarbazepine and carbamazepine, and their active metabolites, MHD and CBZ-10,11-epoxide (CBZ-E). |
CBZ is oxidized by the cytochrome P450 system (CYP3A4 and CYP2C8 isoforms) (43) to CBZ-10,11-epoxide (CBZ-E), which is considered the most important product of CBZ metabolism (Figure 53.1). CBZ-E is an active metabolite that may contribute to rash and other side effects associated with CBZ use (44, 45, 46). CBZ induces the activity of CYP3A4, with the metabolic clearance of CBZ-E nearly doubled in induced patients (47).
CBZ leads to autoinduction, which increases clearance (double in monotherapy), shortens serum half-life, and decreases serum concentrations. This process takes approximately 2 to 6 weeks to occur (36,48, 49, 50).
TABLE 53.1 PHARMACOKINETIC PARAMETERS OF CBZ, OXC, AND MHD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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CBZ-E is hydrolyzed primarily to trans-10,11-dihydroxy-10,11-dihydrocarbamazepine (trans-CBZ-diol). The diol is excreted in the urine and accounts for 35% of a CBZ dose (51). Another, somewhat less important metabolic pathway of CBZ is the hydroxylation at different positions of the six-membered aromatic rings (42). The third most important step in CBZ biotransformation is conjugation reactions. CBZ may be directly conjugated with glucuronic acid. Direct N-glucuronidation of CBZ and its metabolites depends on microsomal uridine diphosphate glucuronosyltransferase (UDPGT) (42). Additionally, CBZ and its phenolic metabolites can be conjugated with sulfuric acid (52).
Drug Interactions
CBZ has a narrow therapeutic range, and plasma concentrations are often maximized to the upper limit of tolerance. As a low-clearance drug, CBZ is sensitive to enzyme induction or inhibition, especially by the large number of agents that induce or inhibit CYP3A4 isoenzymes (53). CBZ as well as its metabolites induce CYP3A4, CYP2C9, CYP2C19, and CYP1A2. As a result, the metabolism of other agents, including AEDs, is increased, which accounts for the decrease in blood levels (50).
The effectiveness of hormonal contraceptives, independent of preparation (oral, subcutaneous, intrauterine, implant, or injectable), can be reduced by CBZ administration. Oral contraceptives should contain ≥50 μg of estrogen. Midcycle spotting or bleeding is a sign that ovulation has not been suppressed (54, 55, 56, 57, 58). On the other hand, agents that interfere with the production of these isoenzymes can have a great effect on plasma levels of CBZ, leading to toxicity. Drugs that inhibit CYPA34 increase plasma concentrations of CBZ. Polytherapy that associates CBZ with inducing and inhibiting other AEDs leads to unpredictable blood levels. Pharmacokinetic interactions among CBZ, OXC, and AEDs are shown in Table 53.2 (39,59). Additional information can be found in Chapter 45.
Efficacy
The efficacy of CBZ in patients with epilepsy was first demonstrated in the early 1960s (60). The agent continues to be a first-line treatment for patients with focal-onset seizures.
Randomized, Monotherapy, Controlled Trials: CBZ versus Other Agents
Most studies (except for the 1985 investigation by Callaghan and colleagues [61]) have demonstrated no difference in efficacy between CBZ and phenytoin (PHT) as monotherapy for adults and children with epilepsy (7,62, 63, 64, 65, 66, 67, 68). No difference in efficacy was reported in trials comparing CBZ and phenobarbital (PB) in children (69), and CBZ and primidone (PRM) for the treatment of partial and generalized seizures (70). The second Veterans Administration (VA) Cooperative Study, a multicenter, randomized, double-blind, parallel-group trial, compared CBZ with valproate (VPA) for the treatment of 480 adults with complex partial (n = 206) or secondarily generalized (n = 274) seizures. The patient population comprised recently diagnosed, AED-naïve patients with epilepsy, as well as those who were being suboptimally treated. In patients with tonic-clonic seizures, there was no difference in efficacy between the two agents. However, CBZ appeared more efficacious than VPA for the treatment of patients with partial seizures, according to several outcome measures: number of seizures, seizure rate, seizure score, and time to first seizure (71,72). Other studies did not reveal any significant differences between CBZ and VPA in adults (73,74) or children (75).
TABLE 53.2 PHARMACOKINETIC INTERACTIONS AMONG CBZ, OXC, AND OTHER ANTIEPILEPTIC DRUGS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Large Trials Comparing Several AEDs with CBZ
The first VA Study was a double-blind, comparative study of monotherapy with PB, PHT, PRM, and CBZ in 622 adults with partial and secondarily generalized tonic-clonic seizures (65). CBZ was found to be similarly as effective as PB, PHT, and PRM in controlling secondarily generalized tonic-clonic seizures. However, CBZ was more effective than barbiturates for the treatment of partial seizures, whether simple or complex. No difference was found between CBZ and PHT.
Other studies in the United Kingdom (68,76) did not demonstrate any differences between CBZ and PB, PHT, or VPA. However, the patients from the United Kingdom had been recently diagnosed with epilepsy, whereas half of the patients in the VA trials had been previously treated. Nevertheless, the large number of patients with complex partial seizures in the VA studies may provide the power to
detect statistically significant differences (72). Because of the above-mentioned data, CBZ has been considered a first-line AED for the treatment of partial and secondarily generalized tonic-clonic seizures, and is used as an active control in trials of all new compounds.
detect statistically significant differences (72). Because of the above-mentioned data, CBZ has been considered a first-line AED for the treatment of partial and secondarily generalized tonic-clonic seizures, and is used as an active control in trials of all new compounds.
Carbamazepine Versus New Antiepileptic Drugs
CBZ has been tested against almost all new AEDs in monotherapy trials. The majority of these studies have shown no difference in efficacy between CBZ and lamotrigine (LTG) in adults, adolescents, and children (79, 80); OXC (90); or topiramate (TPM) in children and adults (81). CBZ was significantly more efficacious than vigabatrin (VGB) (82,83), remacemide (84), and probably gabapentin (GBP) (85). The last study was not designed to compare GBP and CBZ. On the other hand, some of these studies have suggested that GBP (85), LTG (77,78), VGB (82,83), and OXC (80) are better tolerated than CBZ. There are other parameters to be considered before clinical use, however, such as the high incidence of visual field defects associated with VGB (86). These observations preclude VGB as a first-line agent for the treatment of epilepsy, except in special indications.
Based on clinical trials, it is premature to say a definitive word about AED efficacy and safety. There are several methodological limitations in many trials, with some satisfying regulatory agencies but not necessarily guaranteeing clinical use. Most studies are either undertaken with insufficient numbers of patients to demonstrate significant differences or the follow-up is relatively short, considering the seizure-free period, for a true improvement in quality of life to be realized.
According to the available data, we can conclude that CBZ is as effective as any of the other AEDs that have been investigated. More studies that assess the economic impact of epilepsy treatment are warranted to compare several therapies.
Adverse Events
Accurate determination of adverse events has been a limitation in several AED trials. Systematic active questioning of patients has revealed a completely different picture of a spontaneously self-reporting adverse event. The perception of the adverse-event profile can influence a patient’s current health status (87). Although up to 50% of patients treated with CBZ experience adverse events, only 5% to 10% need to discontinue therapy (88).
Neurotoxicity
Most adverse events associated with CBZ use involve the central nervous system (CNS) and are mild, transient, and dose-related; severe idiosyncratic reactions occur rarely. The most common adverse events are nausea, gastrointestinal discomfort, headache, dizziness, incoordination, vertigo, sedation, diplopia or blurred vision (5,72,89, 90, 91), nystagmus, tremor, and ataxia (92). Adverse events are similar in children and more common in elderly patients (88,93).
As with most AEDs, CBZ can cause several psychic disturbances, including asthenia, restlessness, insomnia, agitation, anxiety, and psychotic reactions (94). Neuropsychological adverse events associated with nontoxic, chronic CBZ use are generally minimal (7,28,95,96). Some investigators believe that the use of a sustained-release preparation can be advantageous in both children and adults (92,97).
Hypersensitivity Reactions
The incidence of rash with CBZ use is approximately 10% (65,71,74,75,77). CBZ causes the anticonvulsant hypersensitivity syndrome (AHS), characterized by fever, skin rash, and internal organ involvement (101). AHS is associated with the aromatic AEDs—that is, PHT, PB, PRM, CBZ, and LTG (102,103). AHS begins within 2 to 8 weeks after AED therapy initiation; the reaction usually starts with low- or high-grade fever, and over the next 1 or 2 days a cutaneous reaction, lymphadenopathy, and pharyngitis may develop. Involvement of various internal organs may occur, resulting in hepatic, hematologic, renal, or pulmonary impairment. The most prominent manifestations are hepatitis, eosinophilia, blood dyscrasias, and nephritis. The most common cutaneous manifestation is an exanthema with or without pruritus. Rarely, severe skin reactions may occur, such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (102,103). It is important to the management of the patient to be aware of acute cross-reactivity, which may be as high as 70% to 80% among CBZ, PHT, and PB (101). VPA is considered a safe, acute alternative for the treatment of patients with AHS (104).
Systemic lupus erythematosus may be induced by CBZ. Symptoms generally appear 6 to 12 months after initiation of therapy. Discontinuation of CBZ usually leads to disappearance of the symptoms (105, 106, 107, 108).
Hematologic Effects
Transient leukopenia occurs within the first 3 months of treatment in 10% to 20% of patients taking CBZ (111,112). Persistent leukopenia, which is seen in 2% of patients, reverses with discontinuation of CBZ treatment (113). In the VA study, only one patient had a transient, clinically significant neutropenia (<1000 cells/mm3) associated with CBZ use, and the treatment was not discontinued (72). Isolated thrombocytopenia associated with CBZ treatment has been described at a rate of 0.9 per 100,000 (114). The risk for aplastic anemia in the general population is about
2 to 2.5 per million. Aplastic anemia occurs with CBZ exposure in 5.1 per million (1 per 200,000) (88,114).
2 to 2.5 per million. Aplastic anemia occurs with CBZ exposure in 5.1 per million (1 per 200,000) (88,114).
Endocrinologic Effects
Hyponatremia is an adverse event provoked by CBZ treatment (115, 116, 117, 118). The risk for hyponatremia increases in proportion to the dose of CBZ and age of the patient; it is unusual in children (118).
Although thyroid function tests may be abnormal due to CBZ use, treated patients remain clinically euthyroid (119, 120, 121, 122, 123, 124). Because of the induction effect of CBZ on the metabolism of thyroid hormones, hypothyroid patients may require higher doses of T4 to maintain euthyroid states (125).
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