Itraconazole clozapine

Drugs that might be affected by lopinavir/ritonavir include ergot derivatives, oral contraceptives, antiarrhythmics, HMG-CoA reductase inhibitors, HIV protease inhibitors, atovaquone, calcium channel blockers, ketoconazole, itraconazole, pimozide, cisapride, clarithromycin, disulfiram, metronidazole, immunosuppressants, midazolam, triazolam, narcotic analgesics, rifabutin and rifabutin metabolite, sildenafil, warfarin, bupropion, clozapine, desipramine, piroxicam, quinidine, theophylline, and zolpidem. 

GFJ has been shown to increase the exposure of carbamazepine (175), cisapride (176-179), fluvoxamine (184), losartan (188), methadone (189), scopolamine (191), and sertraline (192). However, only the interaction of GFJ with carbamazepine and cisapride seems to be clinically relevant. No alteration in exposure was observed for clozapine (180,181), heophylline (195), halo-peridol (196), and omeprazole (190). Reports of increased pharmacokinetic parameters of clozapine, theophylline, and haloperidol suggest that an interaction is unlikely to be clinically relevant. Contradicting results were reported for itraconazole (185-187), digoxin (75,183), and sildenafil (193,194). An increased effect on concomitant use of diclofenac and GFJ was observed in rats (182). Overall, the clinical relevance for this drug class appears to be low. 

Itraconazole 200 mg had no significant effect on serum concentrations of clozapine 200-550 mg/day or des-methylclozapine in 7 schizophrenic patients (292). 

Raaska K, Neuvonen PJ. Serum concentrations of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole. Eur J Clin Pharmacol 1998 54(2) 167-70. 

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

A double-blind study in 7 schizophrenic patients taking clozapine found that when itraconazole 200 mg daily was given for a week, no changes in the levels of clozapine or its desmethylclozapine metabolite were seen. A single 50-mg dose of clozapine was given to 5 schizophrenic patients... 

The conclusion is that the cytochrome P450 isoenzyme CYP3A4 is of only minor importance in clozapine metabolism, and that because no interaction takes place between clozapine and itraconazole or ketoconazole, both it and other inhibitors of CYP3A4 can be used with clozapine. However, note that raised clozapine levels have been attributed to treatment with the CYP3A4 inhibitor, erythromycin, see Clozapine + Erythromycin , p.747. 

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