Pharmacotherapeutic Group: antiepileptic, neurotropic, and psychotropic agent. ATC Code: N03 AF01. Dibenzazepine derivative.
Pharmacology: Mechanism of action: The mechanism of action of carbamazepine, the active substance of Tegretol, has only been partially elucidated. Carbamazepine stabilizes hyperexcited nerve membranes, inhibits repetitive neuronal discharges, and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium-dependent action potentials in depolarized neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action.
Whereas reduction of glutamate release and stabilization of neuronal membranes may account mainly for the antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.
Pharmacodynamics: As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and without secondary generalization; generalized tonic-clonic seizures, as well as combinations of these types of seizures.
In clinical studies Tegretol given as monotherapy to patients with epilepsy - in particular children and adolescents - has been reported to exert a psychotropic action, including a positive effect on symptoms of anxiety and depression as well as a decrease in irritability and aggressiveness. As regards cognitive and psychomotor performance, in some studies equivocal or negative effects, depending also upon dosages administered, were reported. In other studies, a beneficial effect on attentiveness, cognitive performance/memory was observed.
As a neurotropic agent Tegretol is clinically effective in a number of neurological disorders, e.g. it prevents paroxysmal attacks of pain in idiopathic and secondary trigeminal neuralgia; in addition, it is used for the relief of neurogenic pain in a variety of conditions, including tabes dorsalis, post-traumatic paresthesia, and post-herpetic neuralgia; in alcohol-withdrawal syndrome it raises the lowered convulsion threshold and improves withdrawal symptoms (e.g. hyperexcitability, tremor, impaired gait); in diabetes insipidus centralis, Tegretol reduces the urinary volume and relieves the feeling of thirst.
As a psychotropic agent Tegretol proved to have clinical efficacy in affective disorders, i.e. as treatment for acute mania as well as for maintenance treatment of (manic-depressive) bipolar affective disorders, when given either as monotherapy or in combination with neuroleptics, antidepressants, or lithium, in excited schizo-affective disorder and excited mania in combination with other neuroleptics, and in rapid cycling episodes.
Clinical Studies: No recent clinical trials have been conducted with Tegretol.
Pharmacokinetics: Absorption: Carbamazepine is absorbed almost completely but relatively slowly from the tablets. The conventional tablets and the chewable tablets yield mean peak plasma concentrations of the unchanged substance within 12 and 6 hours, respectively, following single oral doses. With the oral suspension, mean peak plasma concentrations are attained within 2 hours. With respect to the amount of active substance absorbed, there is no clinically relevant difference between the oral dosage forms. After a single oral dose of 400 mg carbamazepine (tablets) the mean peak concentration of unchanged carbamazepine in the plasma is approx. 4.5 micrograms/mL.
When CR tablets are administered singly and repeatedly, they yield about 25% lower peak concentrations of active substance in plasma than the conventional tablets; the peaks are attained within 24 hours. The CR tablets provide a statistically significant decreased fluctuation index, but not a significant decreased Cmin at steady state. The fluctuation of the plasma concentrations with a twice-daily dosage regimen is low. The bioavailability of Tegretol CR tablets is about 15% lower than that of the other oral dosage forms.
Steady-state plasma concentrations of carbamazepine are attained within about 1 to 2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, as well as on pretreatment status, dosage, and duration of treatment.
The steady-state plasma concentrations of carbamazepine considered as 'therapeutic range' vary considerably interindividually: for the majority of patients a range between 4 to 12 micrograms/mL corresponding to 17 to 50 micromole/L has been reported. Concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite): about 30% of carbamazepine levels.
Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of Tegretol.
Distribution: Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.
Carbamazepine crosses the placental barrier.
Carbamazepine is bound to serum proteins to the extent of 70 to 80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in the plasma (20 to 30%). Concentrations in breast milk were found to be equivalent to 25 to 60% of the corresponding plasma levels.
Biotransformation/metabolism: Carbamazepine is metabolized 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 the pharmacologically active 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 to 24 hours (auto-induction of the hepatic mono-oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment with other liver-enzyme inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9 to 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 400 mg 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.
Special populations: Pediatric patients: Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults.
Geriatric patients (65 years or above): There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with young adults.
Patients with hepatic or renal impairment: No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal function.
Toxicology: Non-Clinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential. However, the animal studies were insufficient to rule out a teratogenic effect of carbamazepine.
Carcinogenicity: In rats treated with carbamazepine for 2 years, there was an increased incidence of hepatocellular tumors in females and benign testicular tumors in males. However, there is no evidence that these observations are of any relevance to the therapeutic use of carbamazepine in humans.
Genotoxicity: Carbamazepine was not found to be genotoxic in various standard bacterial and mammalian mutagenicity studies.
Reproductive toxicity: For reproductive toxicity, see PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL under Use in Pregnancy & Lactation.