Different preparations of carbamazepine may vary in bioavailability; to avoid reduced effect or risk of breakthrough seizures or excessive side effects, it may be prudent to avoid changing the formulation.

Distribution

Carbamazepine is bound to serum proteins to the extent of 70-80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in plasma (20-30%). Concentrations in breast milk were found to be equivalent to 25-60% of the corresponding plasma levels.

Carbamazepine crosses the placental barrier. Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.

Biotransformation

Carbamazepine is metabolised in the liver, where the epoxide pathway of biotransformation is the most important one, yielding the 10, 11-transdiol derivative and its glucuronide as the main metabolites.

Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of carbamazepine 10, 11-epoxide from carbamazepine. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. 9-Hydroxy-methyl-10-carbamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the epoxide pathway.

Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.

Elimination

The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16-24 hours (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other enzyme-inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9-10 hours have been found.

The mean elimination half-life of the 10, 11-epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.

After administration of a single oral dose of 400mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the pharmacologically active 10, 11-epoxide metabolite.

Characteristics in patients

The steady-state plasma concentrations of carbamazepine considered as “therapeutic range” vary considerably inter-individually; for the majority of patients a range between 4-12µg/ml corresponding to 17-50µmol/l has been reported. Concentrations of carbamazepine 10, 11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.

Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults to maintain therapeutic concentrations.

There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.

No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.

5.3 Preclinical safety data
Non-clinical data reveal no special hazard f