Carbamazepine

Indications

• FDA-approved as extended-release capsules (Equetro) for acute manic and mixed episodes of bipolar I disorder in adults.
• FDA-approved for partial seizures with complex symptomatology, generalized tonic-clonic seizures, and mixed seizure patterns in adults and children.
• FDA-approved for the pain of trigeminal neuralgia and glossopharyngeal neuralgia, where it remains the established first-line drug.
• Off-label maintenance treatment of bipolar disorder, generally reserved for patients intolerant of or unresponsive to lithium and valproate.
• Off-label use for alcohol withdrawal, impulsive aggression, and neuropathic pain, with modest evidence relative to newer alternatives.
• Not effective and potentially worsening in absence and myoclonic seizures, which it can aggravate.

Mechanism of action

• Binds voltage-gated sodium channels in the inactivated state, slowing recovery and limiting sustained high-frequency neuronal firing.
• Use-dependent blockade means it suppresses pathologically rapid discharge while sparing normal transmission at physiologic firing rates.
• Reduces glutamate release and modulates calcium currents, contributing to antimanic and antineuralgic effects.
• Acts as an agonist at adenosine A1 receptors and dampens kindling, mechanisms proposed for its mood-stabilizing action.
• Antidiuretic hormone potentiation at the renal tubule explains the frequent hyponatremia that accompanies therapeutic use.

Pharmacokinetics

• Absorption is slow and erratic with peaks at 4 to 8 hours for immediate-release tablets and later for extended-release formulations.
• The half-life is 25 to 65 hours after a single dose but falls to roughly 12 to 17 hours once autoinduction completes at 3 to 5 weeks.
• Carbamazepine induces its own CYP3A4 metabolism, so a dose that was therapeutic in week one is often subtherapeutic by week four.
• The 10,11-epoxide metabolite is pharmacologically active and neurotoxic, and accumulates when valproate inhibits epoxide hydrolase.
• It is a potent inducer of CYP3A4, CYP1A2, CYP2C9, CYP2C19, UGT enzymes, and P-glycoprotein, affecting a very large number of drugs.

Dosing

• For bipolar mania start extended-release 200 mg twice daily and increase by 200 mg per day as tolerated, with a maximum of 1600 mg/day.
• For epilepsy start 200 mg twice daily and titrate weekly by 200 mg to a usual adult range of 800-1200 mg/day in divided doses.
• Trigeminal neuralgia starts lower at 100 mg twice daily, titrated by 200 mg per day to pain control, rarely exceeding 1200 mg/day.
• Expect to raise the dose after 3 to 5 weeks because autoinduction lowers levels; recheck a trough and adjust to 4-12 mcg/mL.
• Reduce doses in hepatic impairment and avoid in significant liver disease; renal impairment needs no routine adjustment.
• Taper over several weeks when stopping, since abrupt withdrawal can precipitate seizures even in patients treated for mood symptoms.

Adverse effects

• Dizziness, diplopia, ataxia, sedation, and nausea are common early and are usually dose-related and improved by slower titration.
• Hyponatremia occurs in up to a quarter of patients, more often in older adults and with concurrent diuretics or SSRIs.
• Benign leukopenia affects roughly 10 percent, while aplastic anemia and agranulocytosis are rare but potentially fatal.
• Morbilliform rash occurs in about 5 to 10 percent, and progression to Stevens-Johnson syndrome or toxic epidermal necrolysis is the feared outcome.
• Drug reaction with eosinophilia and systemic symptoms is associated with HLA-A*3101 and presents with fever, rash, and organ involvement.
• Hepatotoxicity, cardiac conduction delay, and dose-related cognitive slowing round out the effects that most often force a switch.

Monitoring

• Screen patients of Asian ancestry for HLA-B*1502 before the first dose and do not start carbamazepine if the allele is present.
• Obtain a baseline CBC with differential, liver enzymes, sodium, and renal function, and repeat at 2 to 4 weeks and periodically thereafter.
• Check a trough level after 3 to 5 days at a new dose and again after 4 to 6 weeks to capture the drop caused by autoinduction.
• Recheck sodium at 1 month and whenever confusion, headache, or new seizures appear, particularly in patients over 65.
• Instruct patients to report any rash, fever, sore throat, mouth ulcers, bruising, or jaundice immediately and to stop pending evaluation.

Interactions

• As a potent CYP3A4 inducer it lowers concentrations of oral contraceptives, direct oral anticoagulants, many antipsychotics, and immunosuppressants.
• It reduces lamotrigine levels by roughly half, so lamotrigine titration and target dose must be increased when the two are combined.
• Strong CYP3A4 inhibitors such as clarithromycin, fluconazole, diltiazem, and grapefruit juice raise levels quickly into the toxic range.
• Valproate inhibits epoxide hydrolase and raises the neurotoxic 10,11-epoxide even when the parent carbamazepine level looks normal.
• Contraindicated with nefazodone, within 14 days of an MAOI, and in patients with a history of bone marrow depression or prior hypersensitivity.

Special populations

• First-trimester exposure raises the risk of neural tube defects to roughly 0.5 to 1 percent along with craniofacial and cardiac malformations.
• Supplement folic acid at 4 mg/day before conception, and give vitamin K in late pregnancy given induced fetal clotting factor metabolism.
• Milk levels are moderate and breastfeeding is generally acceptable, with monitoring of the infant for sedation, poor feeding, and jaundice.
• Pediatric epilepsy use is established from infancy; children need weight-based dosing and clear faster than adults after induction.
• Older adults are especially prone to hyponatremia, ataxia, falls, and drug interactions, so start low and check sodium early.

Clinical pearls

• Recheck the level at 4-6 weeks; autoinduction routinely drops it into the subtherapeutic range.
• Any new rash on carbamazepine is Stevens-Johnson until proven otherwise; stop the drug and evaluate.
• It induces contraceptive metabolism, so counsel patients to add a non-hormonal method.