Carbamazepine therapeutic range

Assess the AED serum concentration and adjust therapy as needed for agents with a defined therapeutic range (e.g., phenytoin, carbamazepine, valproic acid, and phenobarbital). Drug levels can also be used to determine adherence to medication regimens for agents that do not have defined ranges. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Children (younger than 6 years of age) Ordinarily, optimal clinical response is achieved at daily doses less than 35 mg/kg. If satisfactory clinical response has not been achieved, measure plasma levels to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses greater than 35 mg/kg per 24 hours can be made. 

The anticonvulsant therapeutic range for plasma concentrations of carbamazepine is 4 to 12 pg/mL. Hematological assessment in patients on carbamazepine therapy is appropriate because aplastic anemia and agranulocytosis have been reported in association with its use. 

Approved use for epilepsy therapeutic range of total carbamazepine in plasma is considered the same for children and adults... 

For drugs with short half-lives (30 min to 3 h) and a relatively narrow margin of safety, the use of an inconveniently short dosage interval (< 6 h) would be required to maintain plasma concentrations within the therapeutic range. This situation applies to carbamazepine and valproic acid (anticonvulsants), which are commercially available as conventional oral dosage forms. For drugs with a... 

Dosing and Administration. The variable contributions of the 10,11-epoxide metabolite and free carbamazepine concentrations have restricted a precise definition of the therapeutic range. Loading doses of carbamazepine are indicated only for critically ill patients. During dosage titration, it should be remembered that carbamazepine clearance increases with time. Doses may be started at one-fourth to... 

About 14 days after starting carbamazepine 400 mg daily, a patient taking itraconazole 200 mg daily was noted to have low itraconazole levels (0.15 mg/L), and about 2 months later they were undetectable. About 3 weeks after stopping the carbamazepine, itraconazole levels had reached the therapeutic range (0.36 mg/L). For mention of 2 patients taking carbamazepine with phenytoin, who had undetectable or very low itraconazole levels, and who relapsed or did not respond to itraconazole therapy, see Phenytoin + Azoles , p.552. 

A 58-year-old man, taking carbamazepine 1 g daily for epilepsy developed visual disturbances with diplopia, and was found to have a carbamazepine level of 11 micrograms/mL (therapeutic range 4 to 10 micrograms/mL). Previous levels had not exceeded 5.4 micrograms/mL. The patient said that one month previously he had started to eat one whole grapefruit each day. The levels restabilised at 5.1 micrograms/mL after the carbamazepine dose was reduced to 800 mg daily. ... 

Disorientation, listlessness, aggression, lethargy and, in one case, extreme drowsiness developed in 10 out of 13 patients taking carbamazepine when they were given isoniazid 200 mg daily. Serum carbamazepine levels were measured in 3 of the patients and they were found to have risen above the normal therapeutic range (initial level not stated). ... 

The serum levels of itraconazole 200 mg daily were very low (0.01 to 0.03 mg/L, therapeutic range 0.25 to 2 mg/L) in a patient taking phenobarbital. Two months after stopping the phenobarbital they were higher (0.15 mg/L), but still below the therapeutic range, apparently because carbamazepine had been recently started. For mention of two other patients who had very low itraconazole levels while taking both phenytoin and phenobarbital, see Phenytoin + Azoles , p.552. Some makers of itraconazole say that concurrent use of potent enzyme inducers such as phenobarbital is not recommended. ... 

However, a further study of the efficacy of remaeemide and carbamazepine in combination found fhaf abouf fwo-fhirds offhe 120 patients treated needed 14 to 50% reductions in their carbamazepine dose, to ensure levels remained in the therapeutic range. ... 

The ciclosporin serum levels of a kidney transplant patient fell from 346 to 64 nanograms/mL within 3 days of starting to take carbamazepine 200 mg three times daily. A week later serum levels were down to 37 nanograms/mL. They rose again when the carbamazepine was stopped but fell once more when it was restarted. The ciclosporin dosage was increased to keep the levels within the therapeutic range. ... 

Oxcarbazepine is typically started at a dosage of 150 mg twice a day and titrated by 300 mg/day at weekly intervals. Therapeutic dosages are in the range of 450 mg twice a day to 1,200 mg twice a day. The conversion from carbamazepine to oxcarbazepine is approximately 1 to 1.5. Oxcarbazepine has a higher risk of hyponatremia than does carbamazepine. Serum sodium should be monitored in patients at risk for hyponatremia, such as the elderly or patients who are also taking diuretics. Stevens-Johnson syndrome and toxic epidermal necrolysis may occur between 3 and 10 times more frequently in oxcarbazepine-treated patients than in the general population. Median time from starting treatment to the development of these serious reactions is 19 days. 

Another use of the laboratory is for therapeutic drug monitoring (TDM) of psychotropics with defined optimal ranges, narrow therapeutic indices, or both. Although TDM is not essential for many psychotropics, it is for others, including lithium, several TCAs, valproate, and carbamazepine. It may also be helpful to optimize the use of certain antipsychotics (e.g., haloperidol, clozapine) ( 7). 

The therapeutic concentration range for optimal pharmacological effect of carbamazepine is 4 to 12p,g/mL. Toxicity associated with excessive carbamazepine ingestion occurs at plasma concentrations in excess of 15p.g/mL and is characterized by symptoms of blurred vision, paresthesia, nystagmus, ataxia, drowsiness, and diplopia. Side effects unrelated to plasma concentration include development of an urticarial rash, which usually disappears on discontinuation of the drug, and hematological depression (leukopenia, thrombocytopenia, and aplastic anemia). 

Carbamazepine and valproate if creatinine clearance is <10 mL/min, administer 75% of standard dose combining medications in patients with renal impairment should be done cautiously use agents that have a therapeutic serum concentration range for blood level monitoring... 

The drugs used as antiepileptics are a disparate group, and their interactions need to be considered individually. Carbamazepine and phenytoin have established ranges of therapeutic plasma levels and these are typically fairly narrow. Modest changes in plasma levels may therefore be clinically important. 

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