Dosing Tips

• Higher peak levels occur with the suspension formulation than with the same dose of the tablet formulation, so suspension should generally be started at a lower dose and titrated slowly

• Take carbamazepine with food to avoid gastrointestinal effects

✽ Slow dose titration may delay onset of therapeutic action but enhance tolerability to sedating side effects

• Controlled-release formulations (e.g., Equetro, Carbatrol) can significantly reduce sedation and other CNS side effects

• Should titrate slowly in the presence of other sedating agents, such as other anticonvulsants, in order to best tolerate additive sedative side effects

✽ Can sometimes minimize the impact of carbamazepine upon the bone marrow by dosing slowly and monitoring closely when initiating treatment; initial trend to leukopenia/neutropenia may reverse with continued conservative dosing over time and allow subsequent dosage increases with careful monitoring

✽ Carbamazepine often requires a dosage adjustment upward with time, as the drug induces its own metabolism, thus lowering its own plasma levels over the first several weeks to months of treatment

• Do not break or chew carbamazepine extended-release tablets as this will alter controlled-release properties

Overdose

• Can be fatal (lowest known fatal dose in adults is 3.2 g, in adolescents is 4 g, and in children is 1.6 g); nausea, vomiting, involuntary movements, irregular heartbeat, urinary retention, trouble breathing, sedation, coma

Long-Term Use

• May lower sex drive

• Monitoring of liver, kidney, thyroid functions, blood counts and sodium may be required

Habit Forming

• No

How to Stop

• Taper; may need to adjust dosage of concurrent medications as carbamazepine is being discontinued

✽ Rapid discontinuation may increase the risk of relapse in bipolar disorder

• Epilepsy patients may seize upon withdrawal, especially if withdrawal is abrupt

• Discontinuation symptoms uncommon

Pharmacokinetics

• Metabolized in the liver, primarily by CYP450 3A4

• Renally excreted

• Active metabolite (carbamazepine-10,11 epoxide)

• Initial half-life 26–65 hours (35–40 hours for extended-release formulation); half-life 12–17 hours with repeated doses

• Half-life of active metabolite is approximately 34 hours

✽ Is not only a substrate for CYP450 3A4, but also an inducer of CYP450 3A4

✽ Thus, carbamazepine induces its own metabolism, often requiring an upward dosage adjustment

Drug Interactions

• Enzyme-inducing antiepileptic drugs (carbamazepine itself as well as phenobarbital, phenytoin, and primidone) may increase the clearance of carbamazepine and lower its plasma levels

• CYP450 3A4 inducers, such as carbamazepine itself, can lower the plasma levels of carbamazepine

• CYP450 3A4 inhibitors, such as nefazodone, fluvoxamine, and fluoxetine, can increase plasma levels of carbamazepine

• Carbamazepine can increase plasma levels of clomipramine, phenytoin, primidone

• Carbamazepine can decrease plasma levels of acetaminophen, clozapine, benzodiazepines, dicumarol, doxycycline, theophylline, warfarin, and haloperidol as well as other anticonvulsants such as phensuximide, methsuximide, ethosuximide, phenytoin, tiagabine, topiramate, lamotrigine, and valproate

• Carbamazepine can decrease plasma levels of hormonal contraceptives and adversely affect their efficacy

• Combined use of carbamazepine with other anticonvulsants may lead to altered thyroid function

• Combined use of carbamazepine and lithium may increase risk of neurotoxic effects

• Depressive effects are increased by other CNS depressants (alcohol, MAOIs, other anticonvulsants, etc.)

• Combined use of carbamazepine suspension with liquid formulations of chlorpromazine has been shown to result in excretion of an orange rubbery precipitate; because of this, combined use of carbamazepine suspension with any liquid medicine is not recommended