Carbamazepine

Carbamazepine is FDA indicated for epilepsy, trigeminal neuralgia, and acute manic and mixed episodes in bipolar I disorder.[1][2] Indications for epilepsy are specifically for partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic seizures (grand mal), and mixed seizure patterns.[1] Carbamazepine is not indicated for absence seizures.[3] Carbamazepine is FDA indicated as first-line treatment trigeminal neuralgia or tic douloureux.  A systemic review shows the efficacy of carbamazepine extended-release in bipolar I mania in patients with acute manic or mixed episodes.[4]

Carbamazepine is used off-label for refractory schizophrenia. Simple well designed trials have shown efficacy in patients with schizophrenia with EEG abnormalities, schizophrenia with violent episodes, and schizoaffective disorder. It improves both positive and negative symptoms in schizophrenic patients.[5] Other off-label uses of this drug include treatment of restless leg syndrome and decreasing agitation and aggression in patients with dementia.[6][7] Another prominent off-label use of this drug is the treatment of neuropathic pain and fibromyalgia.[8] In patients with moderate to severe alcohol withdrawal syndrome, carbamazepine has shown to have clinical efficacy in treatment. However, this indication does not have approval from the FDA, and it has not been shown to prevent alcohol withdrawal seizures as compared to benzodiazepines.[9]  Carbamazepine is also used off label for maintenance therapy for bipolar disorder. In comparison trail among carbamazepine, lithium, and valproic acid, patients taking carbamazepine has a higher risk for relapse, yet not elevated by a significant amount.[10]

Carbamazepine is a modulation of voltage-gated sodium channels (VGSC), causing inhibition of action potentials and decreased synaptic transmission. Similarly to other anti-convulsions, carbamazepine is suggested to bind to the alpha subunit of VGSC, specifically at a binding pocket formed by the external pore loop and the pore-lining part of domain IV.[11] Researchers proposed that carbamazepine keeps sodium channel in inactivated states, leading to fewer channels to open, and thus inhibits the generation of action potentials.[1]  Carbamazepine also binds to other voltage-gated ion channels, such as voltage-gated calcium channels.[11] 

Carbamazepine is available as conventional tablets (100mg, 200mg), extended-release tablets (100mg, 200mg, 300mg, and 400mg), suspensions, and solutions. Extended-release tablets cannot be crushed or chewed. Tegretol and Tegretol XR should be taken with food, while Carbatrol capsules may be opened and sprinkled on food. Initial dosing is at 200 twice daily in adults and 100 twice daily in children under 12, slowly increased over time to a minimum effective level. Minimum effective levels in adults and children over 12 years are 800 mg to 1200 mg daily for the treatment of epilepsy. In children from six to 12 years, the effective level for treatment of epilepsy is 400 mg to 800 mg daily.[12]

The most common side effects of carbamazepine include dizziness, drowsiness, ataxia nausea, and vomiting. Although rarer in occurrence, this comes with a black box warning for several severe dermatologic reactions. In patients of Han Chinese ancestry, studies have indicated a strong association between the HLA-B*1502 gene and Steven Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Studies have shown no increased risk with this gene and SJS/TEN in Iranian patients.[13] A meta-analysis of 11 studies with 343 cases of carbamazepine-induced SJS/TEN showed HLB-B*4001, HLB*4601, and HLB*5801 genes were strong protective factors. Patients with Han Chinese ancestry should undergo testing for the HLA-B*1502 gene. Up to 90 % of patients on carbamazepine who have this reaction experience it within the first few months of treatment. Another important allele to consider with this medication is HLA*3101. This allele is present in Japanese, Korean, and European ancestry.[1][14] Retrospective studies show a significantly increased incidence of dermatologic reactions such as Steven Johnson syndrome, Toxic epidemic necrolysis, maculopapular eruptions, and drug reaction with eosinophilia and systemic symptoms (Dress syndrome).[1]

Carbamazepine has another black box warning on agranulocytosis and aplastic anemia.[10]  Other serious side effects include central nervous system depression, hepatotoxicity, confusion, renal toxicity, suicidal ideation, and hyponatremia. Hyponatremia is mild, transient, and reversible.[15]

Due to the mild anticholinergic activity, carbamazepine can increase the risk of delirium in the elderly population. This effect can also lead to urinary retention, increased intraocular pressure, and constipation.[16]

Carbamazepine can exacerbate heart failure patients or even lead to cardiac dysfunction in healthy patients due to its tendency to cause homocysteinemia. Homocysteine is commonly known to increase the risk of cardiovascular disease. Patients with cardiac conduction issues have a higher risk of undergoing atrioventricular (AV) heart block. The use of this drug in patients with an abnormal ECG should be avoided to elude potential second and third-degree AV heart block.

This drug is teratogenic and is a category D drug in pregnancy. Although contraindications to carbamazepine do not include pregnancy, clinicians should only use it if the benefits outweigh the increased risk of congenital malformation. Such malformations include spina bifida, craniofacial defection, cardiovascular cutaneous malformation, hypospadias, and developmental delays. Plasma level is reduced during pregnancy, likely related to increased metabolism. Carbamazepine can cross the placenta,[17] and this drug can also be transferred through breast milk in nursing infants, prompting a design to make of whether to discontinue nursing or discontinue the drug in the mother.[18] Carbamazepine has a relatively low teratogenic effect in comparison to Valproic acid.[19]  Precautions should be taking in mixed seizure disorder that includes atypical absence seizures. There is an increased frequency of generalized convulsions in this group of patients with this drug.

Carbamazepine is contraindicated in patients who have bone marrow depression and are hypersensitive to this drug or tricyclic compounds such as amitriptyline.[20] Before administration, monoamine oxidase inhibitors should be discontinued for a minimum of 14 days. Usage carbamazepine and nefazodone together may result in insufficient plasma concentration of nefazodone. Carbamazepine is contraindicated in use with non-nucleoside reverse transcriptase inhibitors due to interaction with CYP3A4.