Carbamazepine interaction with other drugs

Carbamazepine may interact with other drugs by inducing their metabolism. Valproic acid increases concentrations ofthe 10,11-epoxide metabolite without affecting the concentration of carbamazepine. The interaction of erythromycin and clarithromycin (CYP3A4 inhibition) with carbamazepine is particularly significant. 

Antidepressants are considered to have additive effects, therefore combined use is not recommended. Inhibitors of serotonin reuptake by CNS neurons may interact with other drugs or circumstances which cause serotonin release. The enhancement of the serotonergic effects may produce a life-threatening serotonin syndrome. Drugs which can increase the serotonin level when taken in combination with SSRIs include TCAs, MAOIs, reversible inhibitors of monoamine oxidase, carbamazepine, lithium, or serotoneric substances. These drugs should not be coadministered with SSRIs and they may increase the risks of developing a serotonin syndrome. 

Carbamazepine, phenytoin, pheno-barbital, and other anticonvulsants (except for gabapentin) induce hepatic enzymes responsible for drug biotransformation. Combinations between anticonvulsants or with other drugs may result in clinically important interactions (plasma level monitoring ). 

Oxcarbazepine is chemically and pharmacologically closely related to carbamazepine, but it has much less capacity to induce drug-metabolizing enzymes. This property decreases the problems associated with drug interactions when oxcarbazepine is used in combination with other drugs. The clinical uses and adverse effect profile of oxcarbazepine appear to be similar to those of carbamazepine. 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

One of the important limitations to the widespread use of the macrolides has been the propensity to interact with other commonly administered medications. Serious, sometimes life-threatening, consequences have resulted from the administration of macrolides to patients receiving routine medications including theophylline, carbamazepine, terfenadine, and other frequently prescribed medications [4-6]. Most of these interactions involve inhibition of drug metabolism via cytochrome P-450 microsomal enzyme. However, not all macrolides have been associated with such drug interactions. 

Warfarin is heavily plasma protein-bound (> 97 percent). It therefore interacts with other protein-bound drugs (e.g., carbamazepine, phenytoin, and benzodiazepines) in that binding of warfarin to plasma proteins may displace bound drug that is administered as concurrent therapy. Thus, toxicity may result, due to elevated plasma levels, and the clearance rate of the drug may increase to compensate. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

Coadministration with cisapride, pimozide, or carbamazepine (see Warnings and Drug Interactions) patients who were withdrawn from nefazodone because of evidence of liver injury (see Warning box. Warnings) hypersensitivity to nefazodone or other phenylpiperazine antidepressants. 

Drug interactions involving AEDs are shown in Table 52-5. Phenobarbital, phoiytom, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate gjucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzjrme systems and displaces some drugs from plasma albumin. Felbamate and topiramate can act as inducers with some isoforms and inhibitors with others. 

Pharmacodynamic interactions also occur. In particular, the adverse effects of any drug can be increased by other drugs with similar properties. One example is the reciprocal potentiation of the neurotoxic effects of carbamazepine and lamotrigine in patients taking a combination of these drugs (180). Some drugs (for example ciclosporin, clozapine) have a proconvulsant effect and can reduce the efficacy of antiepileptic drugs. 

A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including carbamazepine (1,45). 

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