Pharmacology

Carbamazepine is a tricyclic compound that contains 2 benzene rings and 1 azepine ring with 1 double bond and 1 amide group.

Pharmacodynamics. Concentrations of carbamazepine equal to those that are effective clinically inhibit sustained repetitive firing of cortical neurons in culture. This action is caused by reduction of currents through sodium channels.

Pharmacokinetics. Carbamazepine undergoes extensive biotransformation in humans, and the major pathway is epoxidation of the double bond of the azepine ring, which is catalyzed by hepatic cytochrome P450 3A4, leading to the formation of carbamazepine 10,11-epoxide.

Most studies indicate that 75% to 85% of orally ingested carbamazepine is absorbed and that the bioavailability varies according to the preparation. Half-life of carbamazepine ranges from 18 to 55 hours. Following multiple-dose treatment, the plasma half-life decreases considerably (6- to 12-hour range) because carbamazepine induces its own metabolism. Pharmacokinetic interactions with a wide range of drugs (listed in the Physicians Desk Reference) affect the metabolism of carbamazepine by either decreasing or increasing its serum concentration.

Formulations/delivery. Intravenous carbamazepine infusions at 70% of oral dose are bioequivalent to oral carbamazepine in patients with normal renal function (32). Intravenous carbamazepine has favorable pharmacokinetics and is well tolerated and safe when used as a short-term substitution for oral formulation and seizure control is unchanged (04).

A controlled-release formulation of carbamazepine delivers the same dose over a longer period as compared to a standard formulation, thereby reducing post-dose peaks of plasma levels as well as associated adverse events (23).

Therapeutic drug monitoring. A sensitive liquid chromatography-tandem mass spectrometry method to simultaneously analyze carbamazepine, oxcarbazepine, and their metabolites in human serum is available for routine analysis in clinical settings (15). An ultra-high-performance liquid chromatography-tandem mass spectrometry method enables simultaneous determination of carbamazepine and its 7 major metabolites in serum of epileptic patients within 5 minutes for effective individualized administration in clinical practice (13).

Pharmacogenetics. Genetic variants in microsomal epoxide hydrolase, a drug-metabolizing enzyme, can be used to predict maintenance doses of carbamazepine. Presence of the human leukocyte antigen (HLA-A)*31:01 allele is associated with carbamazepine-induced hypersensitivity reactions in persons of Northern European ancestry (17). HLA-B*15:02 and HLA-A*31:01 have also been identified as predictive genetic biomarkers for carbamazepine hypersensitivity in pediatric patients from North America with diverse ethnic backgrounds and recommendations for genetic testing have been described in clinical guidelines (01). A study has determined that routine screening for HLA-A*31:01 to reduce the incidence of cutaneous adverse drug reactions in patients being prescribed carbamazepine for epilepsy is cost effective (22). Carbamazepine should be avoided in individuals with positive HLA-B*1502 genotype to reduce the risk of drug-induced toxic epidermal necrolysis (31).

Plasma level of the metabolite carbamazepine-10,11-epoxide is an important biomarker of carbamazepine-induced adverse drug reactions (Fricke-Galindo et al 2018).

Asian patients with epilepsy and the SCN1A rs2298771 polymorphism, especially the GG genotype, may be at risk of carbamazepine resistance (37).

Clinical trials

Several controlled clinical trials in the earlier years of development of carbamazepine established its efficacy as equal to that of phenytoin. Carbamazepine is used as a comparison drug for clinical trials with newer antiepileptic drugs.

Lack of efficacy of carbamazepine can be caused by drug interactions, its use for absence-type seizures, and progression of an underlying brain pathology such as a brain tumor.

A systematic review of controlled clinical trials of carbamazepine for chronic neuropathic pain reports efficacy, but the results should be interpreted cautiously as the trials were of short duration and there were deficiencies in methodology (34).

A systematic review of data from clinical trials does not confirm or refute an advantage for controlled-release carbamazepine over immediate-release carbamazepine for seizure frequency or adverse events in patients with newly diagnosed epilepsy (24).

A systematic review of controlled clinical trials on patients with partial onset seizures showed that carbamazepine is less likely to be withdrawn and that 12-month remission is achieved earlier than with topiramate (18). However, there were no differences between the drugs in outcome in patients with generalized tonic-clonic seizures with or without other seizure types or unclassified epilepsy.

A systematic review of controlled clinical trials on children or adults with partial onset seizures or generalized onset tonic-clonic seizures comparing monotherapy with either carbamazepine or lamotrigine showed that time to first seizure suggested that carbamazepine may be superior in terms of seizure control, but lamotrigine was less likely to be withdrawn (19).

Indications

Carbamazepine is indicated for use in:

Off-label uses

Contraindications

Carbamazepine is not recommended in patients with known hypersensitivity to the drug or to any other tricyclic compound such as amitriptyline.

Carbamazepine should not be used in patients with a previous history of bone marrow depression.

Carbamazepine use should not be combined with that of monoamine oxidase inhibitors because of drug interactions.

Goals and duration of treatment

The aim of therapy is to control seizures, relieve pain in trigeminal neuralgia, and modulate behavior in manic-depressive illness.

Dosing

The dosage range in epilepsy varies between 800 to 1200 mg per day. There is a significant difference in the dose between monotherapy and combination with other antiepileptic drugs. In adults, therapy is started with 200 mg twice a day and increased by 200 mg per week, until the best response is obtained. For children under 12 years of age, treatment is started with 100 mg twice a day and increased by 100 mg per week. During chronic treatment with carbamazepine, doses of 10 mg/kg per day are sufficient to maintain plasma concentrations around 6 mg/L, but higher doses (15 mg) may be necessary if comedications increase the metabolism of carbamazepine. Fluctuations in the levels of carbamazepine can be reduced by sustained-release preparations.

In the case of trigeminal neuralgia, the initial dose of 200 mg twice a day is increased until relief from painful attacks is obtained, and the maintenance dose may be 200 mg 3 to 4 times a day. In elderly patients, therapy should be started with 100 mg twice a day. In alcohol withdrawal syndrome, the initial dose is 200 mg 3 to 4 times a day, and in severe cases, the dose can be raised on the first day to 400 mg 3 times a day. Higher doses may be required for the prophylaxis of manic-depressive illness and can be raised to 1600 mg per day.

Special considerations

Pediatrics. Carbamazepine has been shown to be safe and rapidly effective in neonates with benign familial neonatal epilepsy, even in status epilepticus (27).

Pregnancy. Experimental studies have shown no teratogenic effect of carbamazepine on the fetus, but epidemiological studies suggest that there may be an association of carbamazepine use during pregnancy with congenital malformations of the fetus, including spina bifida. Carbamazepine should be used during pregnancy only if the potential benefits outweigh the risks. Studies have shown the role of folic acid deficiency in the causation of congenital malformations such as spina bifida. Medications that lower folic acid should be avoided, and folic acid supplementation during pregnancy is recommended.

Interactions

Drugs that inhibit CYP3A4 metabolism inhibit carbamazepine metabolism and, thus, increase its serum concentrations. Some of these drugs are:

Drugs that induce CYP3A4 can increase the rate of carbamazepine metabolism and decrease plasma carbamazepine concentrations. These include the following:

Carbamazepine can also affect the pharmacokinetics of other drugs. Carbamazepine greatly reduces the serum concentrations of simvastatin, probably by inducing its metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided. Carbamazepine significantly decreases plasma concentrations of fexofenadine, an antihistaminic, probably due to P-glycoprotein induction in the small intestine (35). Adjunctive treatment with carbamazepine reduces the serum concentration of paliperidone in a dose-dependent manner during treatment of schizophrenia (36).

A double-blind, randomized, crossover study of healthy young women found that carbamazepine decreases levels of low-dose oral contraceptive steroids, resulting in increased breakthrough bleeding, and permits ovulation (07). Therefore, women on carbamazepine therapy are not adequately protected from pregnancy by oral contraceptives.

Long-term carbamazepine therapy leads to increased clearance of the analgesic fentanyl resulting in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement (20).

Current guidelines recommend caution in prescribing concomitant use of direct-acting oral anticoagulants and antiepileptic drugs due to drug-drug interactions leading to potential risk of subtherapeutic anticoagulant concentration and treatment failure. A significant interaction between carbamazepine and apixaban, causing subtherapeutic concentration of the drug, has been reported in a patient with atrial fibrillation who had a transient ischemic attack (08). Measurement of plasma concentration of the anticoagulant can help guide a personalized management and avoid adverse clinical outcomes.

Adverse effects

Carbamazepine is generally a safe drug, but as with any drug that has been in use for over half a century, it has accumulated a long list of adverse events reported to both the manufacturer and health authorities. A number of these have been published in the literature and are included in the Physician's Desk Reference. Absence and myoclonic seizures are known to be aggravated by carbamazepine, but this may occur in some focal epilepsies as well. One case of aggravation of seizures in childhood occipital epilepsy, with posterior sharp and slow-wave high amplitude complexes recorded by EEG, has been reported when carbamazepine was added to valproate (30). Clinical condition and EEG findings improved following withdrawal of carbamazepine.

The adverse events may be idiosyncratic or due to dose-related toxicity. The latter can be managed by lowering the dose and does not necessarily require discontinuation of the medication.

Rapid oral loading of carbamazepine in the emergency department, although effective, is associated with a high rate of adverse effects. Most of the dose-related adverse effects involve the nervous system. The most commonly reported of these are ataxia and nystagmus. Lesions in splenium of corpus callosum have been demonstrated by MRI. There are usually no clinical neurologic manifestations, and the lesions clear up on discontinuation of carbamazepine. Hyponatremia has been reported in 26% of carbamazepine-treated patients and was severe and persistent in 7% of patients (02).

A pro-convulsive carbamazepine metabolite, quinolinic acid, has been detected in drug-resistant epileptic human brain specimen removed at surgery (11). The explanation for this is that a drug-resistant blood-brain-barrier not only impedes drug access to the brain but also may allow the formation of neurotoxic metabolites.

Other systems frequently involved are the skin, the hematopoietic system, and the cardiovascular system. Severe drug eruptions and life-threatening events are rare. Other rare complications include Stevens-Johnsons syndrome and toxic epidermal necrolysis.

Cardiac rhythm disturbances have been reported in patients on carbamazepine within therapeutic doses. A patient with trigeminal neuralgia, who presented with syncope due to atrioventricular block, recovered following discontinuation of carbamazepine and resumption of normal sinus rhythm (05). In another patient with recurrent attacks of dizziness and syncope electrocardiogram revealed 2:1 AV block, and the arrhythmia completely resolved following withdrawal of carbamazepine therapy (06).

Interaction with oral contraceptives may reduce contraceptive efficacy, so an alternative method of contraception should be recommended to women of childbearing age.

A controlled, cross-sectional study showed that epileptic men taking carbamazepine present with changes in hormonal levels, altered semen quality, erectile dysfunction, and a reduction in coital frequency (25). Erectile dysfunction has been reported improved by switching treatment carbamazepine to oxcarbazepine in men with epilepsy (26).

Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with carbamazepine (10). DRESS syndrome is a potentially life-threatening multisystem adverse drug reaction, and reexposure or drug provocation tests must be avoided.

Acute carbamazepine intoxication with neurologic manifestations can be treated with hemodialysis, which is simple, cheap, widespread, and easier to apply compared to hemoperfusion (21).

Several prospective studies involving exposure during pregnancy have shown that carbamazepine therapy increases the rate of congenital anomalies, mainly neural tube defects, cardiovascular and urinary tract anomalies, and cleft palate. Pregnant epileptic women on carbamazepine therapy should be monitored by ultrasound and fetal echocardiography.

Measures for safer use of carbamazepine include monotherapy prescription where possible, an adequate dose titration, knowledge of previous adverse drug reactions in the patient, and routine monitoring of plasma carbamazepine concentrations in symptomatic patients (Fricke-Galindo et al 2018).