Carbamazepine Level 

Updated: Jan 03, 2014
  • Author: Suzanne Bentley, MD, MPH; Chief Editor: Eric B Staros, MD  more...
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Reference Range

Carbamazepine (Tegretol) is an iminostilbene that has been used as a first-line medication for both generalized and partial complex seizure disorders.

The therapeutic reference range of carbamazepine is 4-12 mg/L.

The minimum toxic level is 10 mg/kg.

The toxic concentration/critical laboratory value is greater than 30-40 mg/L.

The Terminal elimination half-life of carbamazepine is 18-55 hours for initial/short-term use and 5-26 hours for long-term use (3-5 weeks of continuous drug therapy). The terminal elimination half-life of 10,11-epoxide (carbamazepine metabolite) is 5-10 hours.

The volume of distribution is 1.4 L/kg (up to 3 L/kg in cases of overdose).

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Interpretation

The carbamazepine level is used to measure the concentration of the drug in a patient’s blood.

The carbamazepine level can be correlated with a patient’s clinical presentation to ascertain the therapeutic carbamazepine level. It is recommended that patients receiving this drug undergo complete blood cell counts and liver function tests checked regularly. If toxicity is suspected, a stat level of carbamazepine should be obtained, followed by repeat levels every 4-6 hours in the case of delayed/prolonged absorption.

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Collection and Panels

Specimen: Whole blood/serum/plasma

Container: Red-top tube (plain, no gel)

Collection method: Routine venipuncture

Draw volume: 2 mL; 0.5-1 mL minimum

When checking carbamazepine levels in a patient on a regular medication regimen, the specimen should be drawn immediately prior to next carbamazepine dose (trough).

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Background

Description

Carbamazepine (Tegretol) is an iminostilbene that has been used as a first-line medication for both generalized and partial complex seizure disorders. In addition, carbamazepine has been used as treatment in patients who have previously abused stimulants, as well as patients with alcohol withdrawal, bipolar disorder (after lithium has been tried), panic attacks, neuropathic pain, trigeminal neuralgia, resistant depression, and certain behavioral disorders. [1, 2]

Carbamazepine produces its effects by inhibiting high-frequency firing of sodium channels and interfering with central nervous system adenosine receptors, muscarinic acetylcholine receptors, nicotinic acetylcholine receptors, and N-methyl-d-aspartate receptors. Blockade of synaptic transmission in the trigeminal nucleus is the mechanism by which carbamazepine alleviates neuropathic pain. One of the side effects of carbamazepine, syndrome of inappropriate antidiuretic hormone secretion, results from the drug’s central antidiuretic effects.

Dosage forms of carbamazepine include 200-mg tablet PO, 100-mg chewable tablet, and 100-mg/5-mL suspension. Extended-release forms are also available as 100-, 200-, and 400-mg tablets. The maximum daily dose is 1.6-2.4 g in adults and 35 mg/kg/day in children. The minimum dose at which life-threatening toxicity have been observed to occur is at 5.8-10 g in adults and 148 mg/kg in children.

Dose-related effects of the drug include sedation and ataxia.

Symptoms of carbamazepine toxicity include manifestations of anticholinergic, CNS depressant, and vestibular-brainstem effects; however, the levels at which various toxicities occur are approximate at best. In mild to moderate overdose, nystagmus, ataxia, ophthalmoplegia, dyskinesia, dystonia, mydriasis may be observed. In particular, ataxia and nystagmus usually occur with serum concentrations greater than 10 mg/L.

Other manifestations that occur with more significant toxicity include seizures, respiratory depression, and coma, which have been observed at serum levels of greater than 40 mg/L. One cardiac manifestation of overdose is sinus tachycardia. Atrioventricular block and bradycardia have also been reported, although mostly in individuals older than 50 years. On electrocardiography, QT and QRS interval prolongation can be observed. QRS widening is usually no longer than 100-120 msec in length and is usually transient.

In patients who are asymptomatic but in whom overdose is suspected, a minimum of 6 hours of observation is suggested and a minimum of 12 hours for those taking extended-release tablets. In addition to airway protection and cardiovascular stabilization and supportive care, various decontamination methods have been suggested. In cases of severe toxicity (ie, carbamazepine level >60 mg/L), charcoal hemoperfusion and high-flux hemodialysis have been observed to be effective for treatment. If a patient presents within one hour of ingestion and is not obtunded, activated charcoal may be given, as prolonged absorption of carbamazepine may occur; however, this has not been found to affect patient mortality or morbidity. Plasma exchange can have utility in pediatric patients with carbamazepine toxicity.

Long-term use of carbamazepine can lead to hepatitis, bone marrow depression (leukopenia and aplastic anemia), renal disease, hyponatremia, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and both neuroleptic malignant syndrome and serotonin syndrome when combined with particular medications. The drug can also decrease T3, T4, and free T4 levels.

Carbamazepine is a teratogen that can cause growth deficiency, fetal malformations (most notably spina bifida), and developmental delay.

Indications/Applications

Carbamazepine is erratically absorbed from the gastrointestinal tract. Peak levels may take as long as 6-24 hours to be attained; this can be longer in extended-release formulas, for which it can take up to 96 hours for peak levels to be reached. Oral-suspension forms of carbamazepine can be absorbed more rapidly in the body, with effects occurring as early as within 30 minutes of ingestion. The volume of distribution is approximately 0.8-1.2 L/kg, which can increase to up to 3 L/kg in cases of carbamazepine overdose.

Carbamazepine is metabolized by the cytochrome P-450 system enzymes 2D6 and 3A4. The 10,11-epoxide metabolite is about 15% of the parent compound in adults and a slightly higher percentage in children. Both the parent and the metabolite have the same level of activity. Carbamazepine is 75%-78% protein bound. Up to 28% of carbamazepine is eliminated in the feces.

Enterohepatic recycling of the drug also occurs. Enterohepatic cycling of carbamazepine coupled with its irregular absorption from the gastrointestinal tract in drug overdose can cause cyclic coma and relapse of the symptoms of toxicity mentioned above. Carbamazepine can induce hepatic microsomal enzymes, thereby decreasing the concentrations of certain medications in the body, including warfarin, oral contraceptives, losartan, methadone, cyclosporine, haloperidol, and quinidine. Conversely, carbamazepine levels can be reduced by erythromycin, isoniazid, nonsteroidal anti-inflammatory (NSAID) drugs excluding aspirin, fluoxetine, verapamil, diltiazem, cimetidine, and propoxyphene.

The elimination half-life of carbamazepine is subject to auto-induction by cytochrome P-450 enzymes. Elimination of this medication varies.

Considerations

Recent studies have examined the prevalence of carbamazepine-related hypersensitivity reactions such as Stevens-Johnson syndrome in certain ethnic groups. The allele HLA-B*1502 has been found to place patients of particular Asian ethnic groups at increased risk of these reactions. In addition, a 2011 study by McCormack et al demonstrated a link between the allele HLA-A*3101 in individuals of Northern European ancestry and the development of maculopapular exanthema (Stevens-Johnson syndrome) in association with carbamazepine. [3]

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