Carbamazepine

Indications for Use

Key indications for use include the following:

• An anti-convulsant (all types of seizures except absence seizures)
  • Carbamazepine has a similar clinical effect to phenytoin, however is particularly effective at treating certain partial seizures
• Chronic neuropathic pain, particularly in trigeminal neuralgia
• Bipolar disorder; effective in acute attacks of mania and long term treatment, but less effective in the depressive phase

Mechanism of Action

Carbamazepine inhibits voltage-gated sodium channels, and at higher concentrations it also inhibits voltage-activated calcium channels. 

Its effect in neuropathic pain can be related to the fact that voltage gated sodium channels are up-regulated by nerve damage and lead to pain. Furthermore in epilepsy, blockade of these channels slows down action potential generation and membrane excitability. 

Carbamazepine preferentially blocks cells that are firing repetitively; the higher the frequency of firing the greater the block. 

Created in Biorender.Created in BioRender. Boucher, M (2026) https://BioRender.com/zlkcitg

Fig 1: Mechanism of Action of Carbamazepine

Pharmacokinetics

Carbamazepine falls under category one with respect to switching anti-convulsant brands (MHRA advice 2017), meaning that patients should be maintained on a specific manufacturer’s preparation. Therefore, when switching between preparations, care must be taken,

If required, suppositories are available however are not bioequivalent to oral formulations. 125mg suppositories are approximately equivalent to 100mg tablets, the dose may require further adjustment based on clinical response. 

Oxcarbazepine and eslicarbazepine are novel agents similar to carbamazepine and are thought to have fewer adverse effects and a lesser effect on metabolising enzymes. Oxcarbazepeine is a pro-drug which is metabolised to a compound similar to carbamazepine. 

Absorption

Slow absorption but high bioavailability (85-100%). Standard release tablets reach Tmax within 12 hours, chewable 6 hours and syrup 2 hours. Modified-release preparations are available, which may reduce peak-related adverse effects. Steady state levels are reached within 1-2 weeks.

Distribution

70-80% bound to plasma proteins. Crosses the placenta, breastmilk concentrations 25-60% of plasma levels. 

Metabolism

Carbamazepine is a substrate for CYP3A4 and also induces hepatic CYP450 enzymes on repeat administration. Induction of these enzymes can increase drug toxicity if the primary metabolite has a toxic effect (e.g. paracetamol) and reduce the clinical effect of the drug, when primary metabolites are inactive. 

Like carbamazepine, inducing agents are often a substrate of the induced enzymes, therefore on repeat administration, pharmacokinetic tolerance to the drug can occur as metabolism to inactive metabolites increases. Due to this effect, carbamazepine therapy starts at a low dose and is increased over a period of weeks, as the enzyme induction effect starts to take effect.

Excretion

Half life 12-18 hours after repeated doses, although initially half life is around 30 hours. Mostly eliminated via kidneys (72%).

Contraindications

• Acute porphyria’s
• AV conduction abnormalities
• History of bone marrow depression 

Cautions and Adverse Effects

Like with other anticonvulsants and enzyme inducers, carbamazepine can cause precipitation of acute porphyria attacks 

Furthermore, carbamazepine has mild anticholinergic activity, therefore adverse effects such as sedation, blurred vision, urinary retention and increased intraocular pressure can occur. 

Haematological effects such as leucopenia and rare aplastic anaemia, and hepatic toxicity may occur, requiring regular monitoring.

Seizure exacerbation can occur in patients with absence or myoclonic seizures, tonic/atonic seizures, dravet syndrome, Lennox-Gastaut syndrome and myoclonic-atonic seizures.

Abrupt Withdrawal

Withdrawal of carbamazepine can lead to seizures; therefore, therapy should be gradually stopped. If abrupt withdrawal is required, an alternative anti-convulsant should be considered. 

Vitamin D deficiency

Carbamazepine, alongside other anticonvulsants (phenytoin, phenobarbital and sodium valproate), can increase metabolism of vitamin D3 via induction of the CYP450 enzyme. This may lead to a vitamin D deficiency, hypocalcaemia and hypophosphataemia. 

As a result of this, patients treated with carbamazepine are at higher risk of osteopenia, osteoporosis and fractures in long term therapy. Vitamin D supplementation should be considered for at-risk patients on long term carbamazepine treatment.

Risk of Suicidal Thoughts and Behaviour

MHRA Alert for all antiepileptics was issued in 2008 after a meta-analysis of placebo controlled trials showed a small increased risk of suicidal thoughts and behaviour

Pregnancy

The risk of congenital malformations is 2-3 times higher in babies born to epileptic mothers. Carbamazepine taken in pregnancy can cause retardation of fetal head growth, spina bifida and malformation of the male urethra. Furthermore, enzyme induction may also cause vitamin K deficiency in neonates.

Pharmacogenomics

Like phenytoin, carbamazepine can cause Stevens-Johnsons syndrome (SJS) and toxic epidermal necrolysis (TEN), and an increased risk is associated with HLA allele, HLA-B*1502. This allele is more common in those from Thai, Malaysian or Taiwanese backgrounds, who may benefit from screening for this allele prior to commencement of treatment. 

The HLA-A*3103 allele may be associated with an increased risk of SJS, TEN and drug rash with eosinophilia (DRESS), however there is insufficient data to support routine screening for this allele. 

Thyroid function

Carbamazepine can reduce concentrations of thyroid hormones via enzyme induction. Patients may require higher doses of thyroid replacement.

Hyponatraemia

Carbamazepine can cause syndrome of inappropriate antidiuretic hormone secretion (SIADH), leading to hyponatraemia in up to 40% of patients. This effect is mediated by increased sensitivity to vasopressin, enhancing water reabsorption in the collecting ducts. 

Monitoring

Baseline monitoring

• Required: BMI, FBC (risk of agranulocytosis, leucopenia, aplastic anaemia), LFTs, U+Es, Na, HLA-B*1502 in at risk ethnic groups
• Consider: Creatinine, reticulocytes, iron, ECG, vitamin D
• Patient should monitor for signs of bone marrow suppression, dermatological or hepatic reactions: fever, sore throat, rash, ulcers, bruising, purpuric haemorrhage 

Continuous monitoring

• After 2 weeks and monthly for 3 months: Na
• Dose change: ECG
• Hypothyroid patients: TFTs within 2-3 months 
• Periodically ongoing: U+E, LFTs, Vitamin D

Therapeutic drug monitoring can be undertaken, however is not recommended as routine monitoring. If a level is taken, it should be taken after 1-2 weeks of a dose change/initiation of therapy, the optimal plasma concentration is 4-12mg/L.

Interactions

CYP-related interactions

Carbamazepine induces its own metabolism, and that of other enzyme inducers such as phenobarbital, rifampicin, griseofulvin, phenytoin, theophylline and ethanol. These enzyme inducers will also induce carbamazepine metabolism leading to a reduction in carbamazepine exposure, however may also raise the active metabolite level leading to increased risk of adverse reactions such as dizziness, drowsiness, ataxia and diplopia. 

In addition to this, carbamazepine also induces the metabolism of other CYP substrates including warfarin, oral contraceptives, tadalafil, corticosteroids and ciclosporin, leading to reduced levels of these substrates.

Oral contraceptives use the minimum effective dose of oestrogen, as increasing dose leads to increasing thromboembolism risk, therefore when combined with enzyme inducers, a loss of active drug can lead to contraceptive failure. This effect also occurs with progesterone only pills.

Induction of enzymes can occur slowly and if therapy with the inducer is stopped, the effect does not diminish immediately.

Co-administration of carbamazepine with CYP3A4 enzyme inhibitors can lead to increased carbamazepine exposure, such as macrolide antibiotics, azole antifungals, diltiazem, verapamil and grapefruit juice. 

Carbamazepine may reduce exposure to DOACs such as rivaroxaban, dabigatran, apixaban and edoxaban.

Other interactions

• Carbamazepine is contraindicated with MAOIs.
• Increased neurotoxicity risk with lithium, metoclopramide and haloperidol

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. 
2. Antiepileptics: adverse effects on bone, MHRA (2014). Available from: Antiepileptics: adverse effects on bone – GOV.UK
3. BNF Carbamazepine [online] Accessed 1/4/26
4. SPS Carbamazepine monitoring. Published 6 July 2021, Last updated 30 January 2026. Available from: Carbamazepine monitoring – NHS SPS – Specialist Pharmacy Service – The first stop for professional medicines advice
5. Tegretol 100mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 1040 Accessed 1/4/26