What is carbamazepine?

What is Carbamazepine?

Carbamazepine is a tricyclic anticonvulsant medication FDA-approved for treating certain types of seizures (partial, tonic-clonic, and mixed) and specific nerve pain conditions (trigeminal and glossopharyngeal neuralgia), though it is widely used off-label for bipolar disorder and other psychiatric conditions. 1

Chemical Structure and Classification

• Carbamazepine is a tricyclic compound structurally related to the antidepressant imipramine 2
• It was initially used in the 1960s for trigeminal neuralgia treatment, then approved as an anticonvulsant in the United States in 1974 2

FDA-Approved Indications

• Epilepsy: Carbamazepine treats partial seizures, tonic-clonic seizures, and mixed seizure patterns 1
• Nerve pain: It is the first-line treatment for trigeminal neuralgia and glossopharyngeal neuralgia, with 70% of patients showing partial or complete pain relief 3
• Important limitation: Carbamazepine is not a regular pain medicine and should not be used for routine aches or pains 1

Off-Label Psychiatric Uses

• Bipolar disorder: Carbamazepine is commonly used for acute mania and mood stabilization in bipolar disorder, though only lithium has FDA approval for this indication in youth aged 12 and older 4
• In pediatric bipolar disorder studies, carbamazepine showed a 38% response rate for mania and mixed episodes 4
• The efficacy in mood disorders appears comparable to lithium, with particular utility in some lithium-nonresponsive illness subtypes 5

Mechanism of Action and Pharmacology

• Carbamazepine is well absorbed orally with high bioavailability 6
• It is 75% bound to plasma proteins, with minimal variation between patients 6
• The drug is metabolized in the liver by oxidation through the cytochrome P450 3A4 pathway before urinary excretion 7, 6
• Active metabolite: Carbamazepine-10,11-epoxide is a major metabolite with potent anticonvulsant activity, typically reaching plasma concentrations 10-50% of the parent drug 6

Therapeutic Drug Monitoring

• Therapeutic blood levels should be maintained between 4-8 mcg/mL (15-40 μmol/L) 8, 6, 9
• The elimination half-life after single doses is approximately 35 hours (range 18-65 hours) 9
• During chronic therapy, the half-life decreases to 10-20 hours due to autoinduction of hepatic metabolism 9
• Blood samples should be drawn 4-6 days after dosing changes to avoid transient elevations 8

Dosing Guidelines

For Trigeminal Neuralgia:

• Initial dose: 200 mg at night 3
• Titration: Increase by 200 mg every 7 days 3
• Maintenance: 400-1200 mg/day divided into 2-3 doses 3

For Mood Stabilization:

• Initial dose: 100 mg twice daily 8
• Titrate to therapeutic blood level of 4-8 mcg/mL 8

For Paroxysmal Kinesigenic Dyskinesia:

• Initial dose: 50 mg 3
• More than 85% of patients achieve complete remission with low doses of 50-200 mg/day 3

For Pediatric Epilepsy:

• Carbamazepine should be offered as first-line therapy for partial onset seizures 10
• Two doses per day are appropriate in most cases, though some patients may benefit from more frequent dosing to avoid side effects related to peak concentrations 9

Critical Safety Warnings

Serious Skin Reactions:

• Carbamazepine can cause rare but potentially fatal skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, most likely within the first four months of treatment 1
• HLA-B*15:02 genetic screening must be performed before initiating treatment, particularly in patients of Asian descent 8, 3, 10
• Symptoms include skin rash, hives, mouth sores, and blistering or peeling skin 1

Hematologic Toxicity:

• Carbamazepine can cause rare but serious blood problems including bone marrow depression 1
• Warning signs include fever, sore throat, recurrent infections, easy bruising, red or purple spots, bleeding gums or nosebleeds, and severe fatigue 1
• Regular monitoring of complete blood count is essential 8

Hepatotoxicity:

• Liver function tests should be checked before initiating therapy 8
• Monthly monitoring is recommended for the first 3 months, then every 3-6 months if stable 8
• Patients with preexisting liver disease require more frequent monitoring 8
• Persistent elevation of liver enzymes may require discontinuation 8

Suicidality:

• Like other antiepileptic drugs, carbamazepine may cause suicidal thoughts or actions in approximately 1 in 500 people 1
• Monitor for new or worsening depression, anxiety, agitation, panic attacks, insomnia, irritability, aggression, or unusual behavioral changes 1

Common Side Effects

• Most frequent adverse effects: Dizziness, drowsiness, and problems with walking and coordination, occurring in 65% of patients compared to 27% on placebo 8
• Most side effects are dose-dependent and transient 8
• Taking carbamazepine at bedtime may help minimize daytime side effects like dizziness 10
• Other common effects include somnolence, headache, nausea, and ataxia 3

Major Drug Interactions

Enzyme Induction by Carbamazepine:

• Carbamazepine is a potent inducer of CYP3A4 and other hepatic oxidative enzymes 7
• It significantly decreases levels of oral contraceptives, warfarin, and corticosteroids 8, 7
• Women using oral contraceptives must be advised of reduced effectiveness and should consider alternative contraception 8
• Other affected medications include tricyclic antidepressants, antipsychotics, other anticonvulsants (valproic acid, clonazepam, ethosuximide, lamotrigine), cyclosporin, theophylline, and chemotherapeutic agents 7

Drugs That Increase Carbamazepine Levels:

• Isoniazid can increase carbamazepine levels, potentially leading to toxicity 8
• Other inhibitors include macrolide antibiotics, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, and danazol 7

Drugs That Decrease Carbamazepine Levels:

• Phenytoin, phenobarbital, and primidone accelerate carbamazepine elimination by stimulating CYP3A4, reducing plasma concentrations 7

Metabolite Interactions:

• Valproic acid, valpromide, and valnoctamide inhibit epoxide hydrolase, causing elevated carbamazepine-10,11-epoxide levels and potential toxicity 7

Special Populations

Pregnancy:

• Carbamazepine may harm the unborn baby 1
• A comprehensive risk-benefit assessment should be performed before conception 3
• For patients with mild manifestations, consider discontinuing therapy before or during pregnancy 3
• Pregnant patients should be enrolled in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334 1
• Some studies indicate increased carbamazepine metabolism during pregnancy, potentially requiring dose adjustments 6

Breastfeeding:

• Carbamazepine passes into breast milk 1
• The decision to breastfeed or take carbamazepine should be made with the healthcare provider; both should not be done simultaneously 1

Pediatric Use:

• The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable to adults 9
• Newborns exposed during fetal life eliminate the drug readily after birth with relatively short half-lives (8.2-28.1 hours), indicating metabolic induction during gestation 9

Absolute Contraindications

• History of bone marrow depression 1
• Known allergy to carbamazepine or tricyclic antidepressants 1
• Current use of nefazodone 1
• Use of monoamine oxidase inhibitors (MAOIs) within the last 14 days 1

Critical Discontinuation Warning

• Do not stop taking carbamazepine suddenly without medical supervision 1
• Abrupt discontinuation can cause serious problems, including status epilepticus (seizures that will not stop) in patients with epilepsy 1
• Any dose changes or discontinuation must be done gradually under physician guidance 1

Practical Monitoring Algorithm

1. Before starting: HLA-B*15:02 genetic test (especially Asian patients), baseline CBC, liver function tests, serum sodium if indicated 8, 10
2. First 3 months: Monthly liver function tests and CBC 8
3. After stabilization: Every 3-6 months monitoring of liver function tests and CBC 8
4. Therapeutic drug monitoring: Check carbamazepine levels 4-6 days after dose changes, target 4-8 mcg/mL 8
5. Ongoing vigilance: Monitor for skin reactions, bleeding, infections, mood changes, and drug interaction effects 1