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Drug Reference

carbamazepine

antiepileptic· Brands: Tegretol, Tegretol XR, Carbatrol, Epitol, Teril, SirtalPO

Mechanism of action
Carbamazepine blocks voltage-gated sodium channels in a frequency-dependent manner, prolonging the inactivated state and reducing repetitive neuronal firing. It also inhibits presynaptic voltage-gated sodium channels, decreasing the release of excitatory neurotransmitters such as glutamate. These actions stabilise neuronal membranes and suppress abnormal electrical activity in the brain, which is responsible for its anticonvulsant and analgesic effects in conditions such as trigeminal neuralgia.
Pharmacokinetics
Carbamazepine is slowly and erratically absorbed after oral administration, with a bioavailability of 70% to 90%. Peak plasma concentrations occur 4 to 8 hours after dosing. It is extensively metabolised in the liver, primarily by CYP3A4, to the active carbamazepine-10,11-epoxide, which is further metabolised and excreted renally. Carbamazepine induces its own hepatic metabolism (autoinduction), which lowers half-life from 25 to 65 hours to 10 to 20 hours after several weeks of treatment. It is about 75% protein bound and crosses the blood-brain barrier.
Indications & dosing

Focal and generalized tonic-clonic seizures

Start with low dose, titrate gradually; monitor for hyponatraemia and blood dyscrasias.

  • adult · PO: 100–400 mg BID · Start with low dose, titrate gradually; monitor for hyponatraemia and blood dyscrasias.

Trigeminal neuralgia

Initiate at 100 mg twice daily, increase every 2-3 weeks as needed.

  • adult · PO: 100–400 mg BID · Initiate at 100 mg twice daily, increase every 2-3 weeks as needed.

Bipolar disorder (mania and prophylaxis)

Use lower doses in elderly or liver disease; monitor serum levels.

  • adult · PO: 200–400 mg BID · Use lower doses in elderly or liver disease; monitor serum levels.
Contraindications & precautions
  • Hypersensitivity to carbamazepine or tricyclic antidepressants · Cross-sensitivity between carbamazepine and tricyclics is possible.
  • History of bone marrow depression · May predispose to agranulocytosis or aplastic anaemia.
  • Porphyria · Carbamazepine can precipitate acute porphyria.
  • Concurrent use of MAOIs (or within 14 days) · Increased risk of hypertensive crisis; initiate carbamazepine after stopping MAOIs.
  • Atrioventricular block (unless pacemaker in situ) · May worsen conduction defects; ECG monitoring advisable if used.
  • Monitor full blood count, liver function tests and serum sodium at baseline and periodically during treatment.
  • Advise patient to report fever, sore throat, mouth ulcers, bruising or bleeding promptly; discontinue if these occur.
  • Counsel patient to stop taking carbamazepine and seek immediate medical attention if a rash develops, especially if blisters, fever or mucosal involvement.
  • Do not withdraw carbamazepine abruptly; reduce the dose gradually to prevent seizure exacerbation.
  • Carbamazepine is a potent CYP3A4 inducer; check and adjust interactions with oral contraceptives, warfarin, other antiepileptics and many other drugs.
  • Start with a low dose and titrate slowly to minimise adverse effects, especially in elderly patients or those with hepatic impairment.
Adverse effects
  • Dizziness
  • Ataxia
  • Diplopia
  • Nausea and vomiting
  • Hyponatraemia (SIADH)serious
  • Maculopapular rash
  • Stevens-Johnson syndrome / toxic epidermal necrolysisserious
  • Blood dyscrasias (agranulocytosis, aplastic anaemia)serious
  • DRESS syndromeserious
  • Hepatic failure or pancreatitisserious
Interactions
  • clarithromycinmajorAvoid coadministration where possible. If combined therapy is necessary, monitor carbamazepine plasma concentrations at baseline and after initiation of clarithromycin, and adjust the carbamazepine dose accordingly. Monitor the patient for clinical signs of toxicity. Consider alternative antibiotics with less CYP3A4 inhibition, such as azithromycin.
  • valproic acidmajorMonitor serum concentrations of both valproic acid and carbamazepine (including free carbamazepine if feasible) at baseline and after any dose change, and monitor for clinical signs of toxicity or inadequate seizure control. Adjust valproic acid dose upwards if levels fall, and consider reducing carbamazepine dose if epoxide toxicity develops. Consider alternative antiepileptic drugs if monitoring is not available or if the interaction proves difficult to manage.
  • theophyllinemajorMonitor serum theophylline concentrations before and after starting or stopping carbamazepine. Adjust the theophylline dose as necessary to maintain therapeutic concentrations and clinical response. Continue monitoring until concentrations are stable. Advise patients to report signs of worsening respiratory symptoms or theophylline toxicity.
  • lamotriginemajorMonitor lamotrigine plasma concentrations and clinical response when carbamazepine is initiated, adjusted, or discontinued. Increase the lamotrigine dose when carbamazepine is added, and decrease it when carbamazepine is stopped. Dose adjustments should be based on therapeutic drug monitoring and the patient's clinical status. Follow local prescribing guidelines and specialist advice.
  • fluoxetinemajorMonitor carbamazepine plasma concentrations and clinical signs of toxicity when starting, stopping, or changing the dose of fluoxetine. Adjust the carbamazepine dose accordingly. Monitor for signs of reduced fluoxetine efficacy and consider alternative antidepressants with less enzyme inhibition if appropriate.
  • ethinylestradiol/levonorgestrelmajorAvoid co-prescribing carbamazepine and combined oral contraceptives. If concurrent use is necessary, use an alternative contraceptive method such as a copper intrauterine device or a barrier method. Consider a progestogen-only method not reliant on CYP3A4, or a higher-dose combined pill, but no method is fully reliable. Counsel on breakthrough bleeding and the need for additional contraception during and for at least 28 days after stopping carbamazepine. Monitor for pregnancy.
  • simvastatinmajorAvoid the combination if possible. If a statin is needed, consider a statin not metabolised by CYP3A4, such as pravastatin or rosuvastatin. If the combination is unavoidable, monitor lipid levels regularly and adjust the simvastatin dose accordingly, with careful consideration of the risk of myopathy when carbamazepine is stopped. Patients should be counselled to report unexplained muscle pain, tenderness, or weakness.
  • warfarinmajorMonitor INR closely, typically within 3 to 5 days of starting or stopping carbamazepine, and adjust the warfarin dose accordingly. Consider an alternative antiepileptic that does not induce hepatic enzymes if possible. Advise patients to report signs of thrombosis or bleeding. When carbamazepine is stopped, the warfarin dose will likely need to be reduced to avoid excessive anticoagulation.
  • erythromycinmajorAvoid co-prescription if possible. If combination is necessary, consider using an alternative macrolide such as azithromycin which has less effect on CYP3A4. If erythromycin must be used, monitor carbamazepine plasma levels closely (e.g., every 2 to 3 days initially) and adjust the carbamazepine dose accordingly. Monitor the patient for signs of carbamazepine toxicity.
  • phenytoinmajorMonitor plasma concentrations of both drugs when initiating, adjusting, or stopping either drug. Adjust doses based on therapeutic drug monitoring. Consider alternative antiepileptics with fewer interactions. Monitor for signs of seizure recurrence or toxicity.
  • fluconazolemajorIf co-prescription is necessary, monitor plasma carbamazepine concentrations and clinical signs of toxicity, especially at the start of fluconazole therapy. Reduce the carbamazepine dose as required. Advise patients to report neurological symptoms.
  • methadonemajorMonitor closely for signs of opioid withdrawal, especially when starting or stopping carbamazepine. Consider increasing the methadone dose as needed, guided by clinical response and therapeutic drug monitoring of methadone concentrations. Adjust the methadone dose when carbamazepine is discontinued to avoid toxicity. Consider alternatives to carbamazepine where possible, or use caution with ECG monitoring if QT prolongation risk is high.
  • rivaroxabanmajorAvoid co-administration if possible. If combined therapy is necessary, monitor patients closely for signs of thrombosis and consider alternative anticoagulants that are not affected by CYP3A4/P-gp induction. If rivaroxaban is continued, consider dose adjustment and regular assessment of thromboembolic risk. Consult local guidelines and specialist advice.
Renal & hepatic adjustment
  • eGFR 0+: No specific dose adjustment required. Use with caution in severe renal impairment, monitor for hyponatremia and toxicity.
  • Hepatic impairment (mild): Use with caution, consider lower initial dose, and monitor serum concentrations.
  • Hepatic impairment (moderate): Reduce dose and monitor closely. Consider alternative therapy if possible.
  • Hepatic impairment (severe): Avoid use or use extreme caution with close monitoring of serum levels. (avoid)
Monitoring, pregnancy & toxicity
  • Plasma carbamazepine concentration · Baseline, after dose changes, and periodically
  • Full blood count (FBC) · Baseline and every 3 to 6 months
  • Liver function tests · Baseline and periodically
  • Serum sodium · Baseline and periodically as symptoms suggest
  • Renal function · Baseline and periodically
  • Skin reactions (SJS/TEN) · Counsel patient to report rash; discontinue if signs appear
  • Pregnancy: Carbamazepine is teratogenic, associated with neural tube defects and other malformations. If used, ensure effective contraception, offer folic acid 5 mg daily before conception, and use the lowest effective dose. For bipolar disorder, consider alternatives; for epilepsy, do not stop abruptly without specialist advice. Discuss risks and benefits with the patient.
  • Toxicity: Neurological: ataxia, nystagmus, diplopia, drowsiness, confusion, seizures, coma. · Supportive care, monitor Glasgow Coma Scale, treat seizures with benzodiazepines.
  • Toxicity: Cardiac: arrhythmias, conduction disturbances, hypotension. · Continuous ECG monitoring; manage arrhythmias per protocol; IV fluids.
  • Toxicity: Gastrointestinal: nausea, vomiting, diarrhoea. · Supportive care; consider activated charcoal if within 1 hour.
  • Toxicity: Hyponatremia (SIADH) causing confusion and seizures. · Check serum sodium; restrict fluids; if severe, hypertonic saline.
Clinical notes
Carbamazepine is used for focal and generalised seizures, trigeminal neuralgia, and bipolar disorder. Treatment is started at low doses and titrated slowly to minimise adverse effects such as drowsiness, dizziness, and hyponatraemia. Because of enzyme induction, carbamazepine can reduce the efficacy of many drugs, including oral contraceptives and warfarin. It is also associated with serious skin reactions, so patients should be advised to report bruising, rash, or mouth ulcers. Therapeutic drug monitoring is useful, with a reference range of 4 to 12 mg/L, and this also helps detect toxicity. It is teratogenic, so counselling is essential for women of childbearing potential.

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BNF; local formulary