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Belliotti T. The compound was developed and introduced into clinical practice as an antiepileptic drug in in the United Kingdom and Switzerland. It was initially used in the s for the treatment of trigeminal neuralgia in the United States and was approved later for the treatment of epilepsy. Classical reviews of carbamazepine include 2 monographs 29 ; Carbamazepine is a tricyclic compound that contains 2 benzene rings and 1 azepine ring with 1 double bond and 1 amide group.
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. 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 P 3A4, leading to the formation of carbamazepine 10,epoxide.
Half-life of carbamazepine ranges from 18 to 55 hours. Following multiple-dose treatment, the plasma half-life decreases considerably 6- to 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.
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 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 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 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 Genetic variants in microsomal epoxide hydrolase, a drug-metabolizing enzyme, can be used to predict maintenance doses of carbamazepine.
Plasma level of the metabolite carbamazepine,epoxide is an important biomarker of carbamazepine-induced adverse drug reactions Fricke-Galindo et al Asian patients with epilepsy and the SCN1A rs polymorphism, especially the GG genotype, may be at risk of carbamazepine resistance 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 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 A systematic review of controlled clinical trials on patients with partial onset seizures showed that carbamazepine is less likely to be withdrawn and that month remission is achieved earlier than with topiramate 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 Generalized tonic-clonic grand mal seizures and complex partial seizures. Carbamazepine is not effective in absence-type seizures and may even aggravate the occurrence of absence seizures.
Carbamazepine is not recommended in patients with known hypersensitivity to the drug or to any other tricyclic compound such as amitriptyline. Carbamazepine use should not be combined with that of monoamine oxidase inhibitors because of drug interactions. The aim of therapy is to control seizures, relieve pain in trigeminal neuralgia, and modulate behavior in manic-depressive illness.
The dosage range in epilepsy varies between to 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 mg twice a day and increased by mg per week, until the best response is obtained. For children under 12 years of age, treatment is started with mg twice a day and increased by mg per week. Fluctuations in the levels of carbamazepine can be reduced by sustained-release preparations.
In the case of trigeminal neuralgia, the initial dose of mg twice a day is increased until relief from painful attacks is obtained, and the maintenance dose may be mg 3 to 4 times a day. In elderly patients, therapy should be started with mg twice a day. In alcohol withdrawal syndrome, the initial dose is mg 3 to 4 times a day, and in severe cases, the dose can be raised on the first day to mg 3 times a day.
Higher doses may be required for the prophylaxis of manic-depressive illness and can be raised to mg per day. Carbamazepine has been shown to be safe and rapidly effective in neonates with benign familial neonatal epilepsy, even in status epilepticus 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.
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.
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