Carbamazepine with macrolides

Significant increases in serum carbamazepine concentrations due to reduced clearance (97) and prolonged half-life (98,122,123) can result in confusion, somnolence, ataxia, vertigo, nausea, and vomiting in patients taking macrolides (100,124,125). Toxicity can occur rapidly after addition of the macrolide and abate quickly on withdrawal (126). However, a retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interaction in patients who were also taking carbamazepine (127,128). 

Clinically important, potentially hazardous interactions with antihistamines, azole antifungals, benzodiazepines, carbamazepine, cimetidine, delavirdine, diazepam, erythromycin, HIV protease inhibitors, ketorolac, macrolide antibiotics, neuroleptics, phenobarbital, phenytoin, rifampin, ritonavir... 

Often accompanied by a high fever, AGEP is most frequently associated with acetaminophen, carbamazepine, penicillin and macrolide antibiotics, and usually occurs within 24 hours of the drug exposure. 

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. 

It seems probable that clarithromycin, erythromycin and troleandomycin, and to a lesser extent some of the other macrolides, slow the rate of metabolism of the carbamazepine by the cytochrome P450 isoenzyme CYP3A4 so that the anticonvulsant accumulates within the body." " Telithromycin is predicted to interact similarly." It was suggested that the carbamazepine toxicity seen with roxithromycin may have been mediated by P-glycoprotein inhibition, which occurred as a result of an interaction between roxithromycin and atorvastatin. 

Analysis of the macrolide/carbamazepine interactions has shown that patients requiring high doses of carbamazepine to reach therapeutic levels are likely to have a greater rise in their carbamazepine levels." The extent of the interactions is also correlated with the macrolide dose." ... 

A patient phenobarbital and carbamazepine had a modest fall in plasma phenobarbital levels from about 40 to 31 micrograms/mL, and a rise in carbamazepine levels, when given troleandomycin. The general importance of this single report is uncertain, but this modest is probably of limited clinical importance. For a discussion of the rise in carbamazepine levels with troleandomycin, see Carbamazepine + Macrolides, p.531. 

Carbamazepine levels are increased by CYP3A4 inhibitors (cimetidine, macrolides, diltiazem, fluoxetine, ketoconazole, verapamil, valproate) levels are decreased by CYP3A4 inducers (cisplatin, doxorubicin, felbamate, phenobarbital, phenytoin, primidone, rifampin, theophylline). Carbamazepine may increase levels of clomipramine, phenytoin, and primidone and lithium toxicity may decrease levels of phenytoin, warfarin, oral contraceptives, doxycycline, theophylline, haloperidol, alprazolam, clozapine, ethosuximide, and valproate may interfere with other anticonvulsants. 

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