Carbamazepine is an iminodibenzyl derivative desig nated chemically as 5H-dibenzo[b,f]azepine- 5-carboxamide. It is structurally related to the tricyclic antidepressants. It was first introduced into clinical practice in 1962, mainly for the treat ment of trigeminal neuralgia prior to becoming the main AED for focal epilepsies.
UK-SmPC: Epilepsy – generalised tonic-clonic and partial seizures. Carbamazepine Retard is indicated in newly diagnosed patients with epilepsy and in those patients who are uncontrolled or unable to tolerate their current anti-convulsant therapy.
Note: Carbamazepine is not usually effective in absences (petit mal) and myoclonic seizures. Moreover, anecdotal evidence suggests that seizure exacerbation may occur in patients with atypical absences.
FDA-PI: Carbamazepine is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:
- Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.
- Generalized tonic-clonic seizures (grand mal).
- Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by carbamazepine.
Carbamazepine is the superior drug for the treatment of focal epilepsies of any type (idiopathic or symptomatic) with or without secondarily GTCS. It is also licensed for the treatment of primarily GTCSs. In numerous comparative studies, no other drug showed better efficacy than carbamazepine in focal seizures. However, carbamazepine is ineffective and contraindicated in idiopathic generalised epilepsies (IGEs) and epileptic encephalopathies. It is probably ineffective in neonatal and febrile seizures.
Dosage and titration
'Start low and go slow' is important when initiating carbamazepine treatment in order to minimise ADRs.
Adults and children over 12 years of age: start treatment with 200 mg/day in two equally divided doses and increase at weekly intervals in increments of 200 mg/ day up to a total of 800–1200 mg/day. Rarely, higher doses of up to 1800 mg/day are needed.
Children 6–12 years old: start with 100 mg/day in two equally divided doses and increase at weekly intervals in increments of 100 mg/day up to a total of 600–1000 mg/day.
Children under 6 years: start with 10–20 mg/kg/day in two or three divided doses and increase at weekly intervals in increments of 10–20 mg/kg/day up to a maintenance dose of no more than 35 mg/kg/day.
There is a significant difference between the carbamazepine dose given as monotherapy and that used in combination with other AEDs. Higher doses may be necessary in polytherapy with enzyme-inducing AEDs, which increase the metabolism of carbamazepine.
Dosing: two or three times daily.
Fluctuations in the levels of carbamazepine can be reduced by the use of sustained-release preparations.
The clearance of carbamazepine in children is faster than in adults and therefore three- and, sometimes, four-times daily dosing may be required.
Therapeutic Drug Monitoring: useful but substantial diurnal variation in plasma concentrations is common and symptoms of toxicity due to carbamazepine epoxide may occur without increases in carbamazepine levels.
Reference range: 3–12 mg/l (12–50 μmol/l). Carbamazepine epoxide: up to 9 μmol/l.
Developing diplopia may be a good indicator of maximum tolerated carbamazepine levels or epoxide toxicity when carbamazepine levels are within the target range.
Frequent and/or important: sedation, headache, diplopia, blurred vision, rash, gastrointestinal disturbances, ataxia, tremor, impotence, hyponatraemia and neutropenia. CNS-related ADRs are usually dose related and appear on initiation of treatment.
Dose-related reduction in neutrophil count occurs in 10–20% of patients treated with carbamazepine, but it rarely drops below 1.2X10 (Farrell et al., 2008) The vast majority of cases of leucopenia have not progressed to the more serious conditions of aplastic anaemia or agranulocytosis. Nonetheless, complete pretreatment haematological testing should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence for significant bone marrow depression develops.
Hyponatraemia occurs in around 5% of treated patients (see oxcarbazepine). Most physicians advise obtaining blood counts at baseline and every 6–8 weeks for the first 6 months of carbamazepine treatment.
Other: Carbamazepine has shown mild anticholinergic activity; patients with increased intraocular pressure should therefore be warned and advised regarding possible hazards.
Serious: allergic skin rash is the most common idiosyncratic ADR that occurs in 5–10% of patients (probably reduced by half with slow titration of controlled-release carbamazepine). This is usually mild and develops within the first 2–6 weeks of treatment. Carbamazepine should immediately be withdrawn if a skin rash develops in order to prevent serious and sometimes life-threatening conditions, such as anticonvulsant hypersensitivity syndrome. Hepatotoxicity usually occurs in the setting of a generalised hypersensitivity response.
HLA-B*1502 (Kaniwa et al., 2008; Ferrell et al., 2008; Miller, 2008; Locharernkul et al., 2008) in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome when treated with carbamazepine. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine. If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLAB* 1502 have a low risk of Stevens-Johnson syndrome, although the reactions may still very rarely occur. It is not definitely known whether all individuals of south east-Asian ancestry are at risk due to lack of data. The allele HLA-B*1502 has been shown not to be associated with Stevens-Johnson syndrome in the Caucasian population.
The risk for aplastic anaemia and agranulocytosis is five to eight-times greater than in the general population, which is very low.
Cardiac conduction disturbances are rare and mainly occur in susceptible patients (those with pre-existing cardiac abnormalities and the elderly). These are re-assessed (Persson et al., 2003; Saetre et al., 2009) in view of cardiac conduction abnormalities now highlighted with newer AEDs.
FDA warning: All patients who are currently taking or starting on carbamazepine for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression .
Considerations in women
Pregnancy: category D. Contrary to previous studies, recent pregnancy registries are consistent in the finding that risk of teratogenicity with carbamazepine is relatively small (Morrow, 2007). In a recent study the major congenital malformation (MCM) rate for pregnancies exposed only to carbamazepine was 2.2% (1.4–3.4%), which is less than the MCM rate for women with epilepsy who had not taken AEDs during pregnancy (3.5% [1.8–6.8%]; n=239) (Morrow et al., 2006).
Main mechanisms of action
Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. Its main mechanism of action appears to be the prevention of repetitive firing of sodium-dependent action potentials in depolarised neurons via use- and voltage-dependent blockade of sodium channels.
Whereas reduction of glutamate release and stabilisation of neuronal membranes may account for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.
Oral bioavailability: 75–85%. It is unaffected by food intake. Bioavailability may be reduced by up to 50% when stored in hot humid conditions. The slow release formulation shows about 15% lower bioavailability than standard preparations. After oral administration, absorption is relatively slow and often erratic, reaching peak plasma concentrations within 4–24 hours; 75– 85% of orally ingested carbamaze pine is absorbed. Absorption and bioavailability vary among different carbamazepine formulations. Slow-release formulations show about 15% lower bioavailability than standard preparations and have a prolonged absorption phase. Syrup formulations reach maximum plasma concentration faster than chewable or plain tablets.
There are significant diurnal variations in the plasma concentrations of carbamazepine. This is greater in children than in adults, which can result in intermittent ADRs that demand adjustments to the daily dosing.
Protein binding: 66–89%.
Metabolism: carbamazepine is extensively metabol ised in the liver. The predominant elimination pathway leads to the formation of carbamazepine 10,11-epoxide, which is a stable and pharmacologically active agent with its own anti-epileptic activity and ADRs.
Carbamazepine epoxide makes a greater contribu tion to the pharmacological effects (both beneficial and toxic) of carbamazepine in children than in adults. This is because children metabolise carbamazepine more rapidly than adults and this results in carbamazepine epoxide concentrations approaching those of carbamazepine.
Carbamazepine is a potent enzyme inducer. It also induces its own metabolism (autoinduction) by simulating the activity of the cytochrome P450 (CYP) subenzyme 3A4. Autoinduction is usually completed within 3–5 weeks. The half-life of carbamazepine decreases considerably from 18–55 hours to 6–18 hours as autoinduction takes place. In practical terms, this means that carbamazepine levels fall significantly (by about 50%) after several weeks of treatment, which may result in seizure recurrence within this period of autoinduction.
Elimination half-life: 5–26 hours. In combination treatment, the elimination half-life of carbamazepine is reduced by enzyme inducers and increased by enzyme inhibitors.
(Patsalos, 2005; Patsalos & Perucca, 2003a,2003b)
With other AEDs
- Carbamazepine metabolism is highly inducible by certain AEDs.
- Enzyme-inducing AEDs, such as phenobarbital, phenytoin and primidone, cause significant reduc tions in plasma concentrations of carbamazepine. Furthermore, AEDs exacerbate and often double the diurnal variation of plasma carbamazepine concentrations, thus increasing the risk of transient ADRs.
- Valproate markedly increases carbamazepine epoxide levels (sometimes fourfold) without concurrent changes in carbamazepine plasma concentration.
- Co-medication with lamotrigine may cause neurotoxic symptoms of headache, nausea, diplopia and ataxia, probably as the result of a pharmacodynamic interaction and not by increasing carbamazepine epoxide (as originally suggested). Conversely, carmabazepine decreases plasma levels of lamotrigine.
- Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity.
Major: carbamazepine increases the metabolism and therefore decreases the efficacy of a wide variety of drugs, such as oral contraceptives, theophylline, oral anticoagulants and beta-blockers.
Macrolide antibiotics, such as erythromycin, inhibit carbamazepine metabolism and have been associated with carbamazepine toxicity. Carbamazepine toxicity is observed shortly after starting erythromycin therapy, is rapidly reversed on withdrawal of the antibiotic, but can be severe if not recognised early.
Combination therapy with monoamine oxidase inhibitors should be avoided, because carbamaze pine has structural similarities with tricyclic anti depressants. Potential: additive cardiotoxicity with calcium channel blockers and beta-blockers.
Idiosyncratic and other ADRs, drug–drug interactions, the need for laboratory testing and relatively narrow spectrum of anti-epileptic efficacy.
Although carbamazepine is the best AED in the treat ment of focal seizures and secondarily GTCSs, it offers no benefit in most other epilepsies, where it is either ineffec tive or seizure exacerbating. It exaggerates myoclonic jerks, absences and atonic seizures (Chaves et al., 2005; Genton et al., 2000; Parker et al., 1998) Exceptionally, carbamazepine may exaggerate seizures in Panayiotopoulos syndrome and rolandic epilepsy and may induce non-convulsive status and features of serious atypical evolutions (Kikumoto et al., 2006).
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- Kaniwa N, Saito Y, Aihara M et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008;9:1617-22.
- Ferrell PB, Jr., McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 2008;9:1543-6.
- Miller JW. Of race, ethnicity, and rash: the genetics of antiepileptic drug-induced skin reactions. Epilepsy Curr 2008;8:120-1.
- Locharernkul C, Loplumlert J, Limotai C et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 2008;49:2087-91.
- Persson H, Ericson M, Tomson T. Carbamazepine affects autonomic cardiac control in patients with newly diagnosed epilepsy. Epilepsy Res 2003;57:69-75.
- Saetre E, Abdelnoor M, Amlie JP et al. Cardiac function and antiepileptic drug treatment in the elderly: A comparison between lamotrigine and sustained-release carbamazepine. Epilepsia 2009.
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- Patsalos PN. Anti-epileptic drug interactions: A clinical guide. Cranleigh, UK: Clarius Press Ltd, 2005.
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- Chaves J, Sander JW. Seizure aggravation in idiopathic generalized epilepsies. Epilepsia 2005;46 Suppl 9:133–9.
- Genton P, Gelisse P, Thomas P, Dravet C. Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology 2000;55:1106–9.
- Parker AP, Agathonikou A, Robinson RO, Panayiotopoulos CP. Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Dev Med Child Neurol 1998;40:517–9.
- Kikumoto K, Yoshinaga H, Oka M, Ito M, Endoh F, Akiyama T, et al. EEG and seizure exacerbation induced by carbamazepine Panayiotopoulos syndrome. Epileptic Disord 2006;8:53–6.