CARBAMAZEPINE
Clinical safety rating: avoid
Induces CYP450 enzymes reducing levels of many drugs (eg oral contraceptives warfarin) HLA-B*1502 allele increases risk of serious skin reactions in certain populations.
Carbamazepine stabilizes the inactivated state of voltage-gated sodium channels, thereby reducing neuronal excitability and repetitive firing. It also potentiates GABAergic transmission and affects calcium and potassium channels.
| Metabolism | Hepatic metabolism primarily via CYP3A4 to carbamazepine-10,11-epoxide (active metabolite). Also metabolized by CYP2C8 and other pathways. Induces its own metabolism (autoinduction) as well as CYP3A4, CYP1A2, CYP2C9, and UGT enzymes. |
| Excretion | Renal: 72% (primarily as metabolites including carbamazepine-10,11-epoxide, with ~1-3% as unchanged drug); Fecal: 28% via biliary elimination. |
| Half-life | Initial: 25-65 hours (single dose), then 12-17 hours (chronic dosing due to autoinduction). Clinical context: autoinduction reduces half-life over 3-5 weeks; adjust dosing accordingly. |
| Protein binding | 75-90% bound, primarily to serum albumin and alpha-1-acid glycoprotein. Binding may decrease in uremic patients. |
| Volume of Distribution | 0.8-1.4 L/kg, indicating extensive tissue distribution (e.g., brain, liver). Clinical meaning: loading doses may be needed for rapid effect. |
| Bioavailability | Oral immediate-release: 75-85% (due to incomplete absorption and first-pass metabolism). Extended-release: 75-85% with slower absorption. No parenteral form. |
| Onset of Action | Oral immediate-release: 4-8 hours for antiepileptic effect; oral extended-release: 12-24 hours. No parenteral route available. |
| Duration of Action | Immediate-release: 12-24 hours; extended-release: 24-48 hours. Clinical note: extended-release provides more stable concentrations; autoinduction may reduce duration. |
| Molecular Weight | 236.27 |
Initial 200 mg orally twice daily, increase by 200 mg/day every 7 days; usual maintenance 800-1200 mg/day in divided doses (max 1600 mg/day).
| Dosage form | TABLET |
| Renal impairment | GFR 30-60 mL/min: administer 75% of normal dose at normal intervals; GFR <30 mL/min: administer 50-75% of normal dose at normal intervals; hemodialysis: supplemented dose of 200-300 mg after dialysis. |
| Liver impairment | Child-Pugh class A: no adjustment; Child-Pugh class B: reduce dose by 25-50% and monitor levels; Child-Pugh class C: contraindicated. |
| Pediatric use | 6-12 years: initial 100 mg orally twice daily, increase by 100 mg/day every 7 days; usual maintenance 400-800 mg/day in divided doses. <6 years: initial 10-20 mg/kg/day in divided doses, increase every 7 days; usual maintenance 10-20 mg/kg/day (max 35 mg/kg/day). |
| Geriatric use | Initiate at 100 mg orally twice daily, increase slowly; monitor serum levels; avoid in patients with unstable gait or cognitive impairment. |
| 1st trimester | Carbamazepine crosses the placenta and is associated with increased risk of neural tube defects (e.g., spina bifida) and other congenital malformations (e.g., craniofacial defects, cardiovascular anomalies) when used during first trimester. Folic acid supplementation recommended. Use only if benefit outweighs risk. |
| 2nd trimester | Continued risk of neurodevelopmental effects and low birth weight. May cause transient neonatal hepatic dysfunction. Monitor fetal growth. Use lowest effective dose. |
| 3rd trimester | Risk of neonatal bleeding due to vitamin K deficiency (carbamazepine induces hepatic enzymes). Administer vitamin K to mother before delivery. Neonatal withdrawal possible. Monitor for coagulopathy. |
Clinical note
Induces CYP450 enzymes reducing levels of many drugs (eg oral contraceptives warfarin) HLA-B*1502 allele increases risk of serious skin reactions in certain populations.
| FDA category | Positive |
| Placental transfer |
■ FDA Black Box Warning
Aplastic anemia and agranulocytosis. Carbamazepine may cause potentially fatal blood dyscrasias. Obtain baseline and periodic CBCs. In patients of Asian ancestry, test for HLA-B*1502 allele before starting, as it increases risk of Stevens-Johnson syndrome.
| Common Effects | trigeminal neuralgia |
| Serious Effects |
History of bone marrow depression (e.g., agranulocytosis, aplastic anemia)Hypersensitivity to carbamazepine or tricyclic antidepressants (cross-sensitivity)Use of MAOIs within past 14 daysAtrioventricular blockPorphyria (acute intermittent or variegate)
| Precautions | Hematologic toxicity (monitor CBC), dermatologic reactions (SJS/TEN, especially HLA-B*1502 positive), hyponatremia (SIADH), hepatic effects (LFT monitoring), cardiac conduction abnormalities (AV block), CNS depression, fetal harm (pregnancy category D), lactation caution, withdrawal seizures (abrupt discontinuation), drug interactions (CYP450 induction), monitoring drug levels (therapeutic range 4-12 mcg/mL). |
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| Carbamazepine readily crosses the placenta with cord blood concentrations approximately 50-80% of maternal serum levels. Fetal concentrations are similar to maternal levels. |
| Breastfeeding | Carbamazepine is excreted into breast milk at low concentrations (milk-to-plasma ratio ~0.4). Infant serum levels are typically subtherapeutic. Adverse effects in infants are rare but may include drowsiness, poor sucking, and rash. Monitor infant for jaundice or hepatic effects. May interfere with vitamin K metabolism. Generally considered compatible with breastfeeding if infant is observed. |
| Lactation Rating | L2 (Possibly Safe) |
| Teratogenic Risk | First trimester: Major congenital malformations (neural tube defects, craniofacial defects, cardiovascular anomalies) in 2-3% of exposed fetuses; dose-dependent risk. Second/third trimester: Impaired fetal growth, neonatal withdrawal syndrome, transient hepatic toxicity, coagulopathy due to vitamin K deficiency. Fetal anticonvulsant syndrome possible. |
| Fetal Monitoring | Maternal: Carbamazepine serum levels (especially free levels), hepatic function, CBC, sodium, thyroid function. Fetal: High-resolution ultrasound at 18-20 weeks (fetal anatomy), fetal echocardiography, serial growth scans. Neonatal: Vitamin K prophylaxis, monitor for withdrawal, coagulopathy. |
| Fertility Effects | Carbamazepine may increase clearance of sex hormones, potentially reducing efficacy of hormonal contraceptives. No direct evidence of impaired fertility in women; limited data on male fertility (possible sperm abnormalities). |
| Food/Dietary | Grapefruit/grapefruit juice can increase carbamazepine levels; avoid concurrent consumption. High-fat meals may increase absorption of some formulations; take consistently with regard to meals. No other significant food interactions known. |
| Clinical Pearls | Carbamazepine is a potent CYP3A4 inducer, reducing efficacy of oral contraceptives, warfarin, and many antiepileptics. Monitor CBC and LFTs at baseline and periodically due to risk of agranulocytosis and hepatotoxicity. Therapeutic drug monitoring (target trough 4-12 mg/L) is recommended. Start low and titrate slowly to minimize dizziness and ataxia. HLA-B*1502 screening is mandatory in Asian populations due to risk of Stevens-Johnson syndrome. Avoid in patients with AV block or history of bone marrow suppression. |
| Patient Advice | Take with food to reduce gastrointestinal upset. · Do not crush or chew extended-release tablets; swallow whole. · Avoid abrupt discontinuation; taper under medical supervision to prevent seizure rebound. · Report any signs of infection (fever, sore throat), easy bruising/bleeding, or jaundice immediately. · Use effective non-hormonal contraception as carbamazepine reduces efficacy of oral contraceptives. · May cause dizziness or drowsiness; avoid driving until individual response known. · Alcohol may worsen side effects; limit or avoid consumption. |