Voriconazole Phenytoin

Coadministration with phenytoin Phenytoin may be coadministered with voriconazole if the IV maintenance dosage of voriconazole is increased to 5 mg/kg every 12 hours. 

Drugs that affect voriconazole include the following barbiturates (long acting), cimetidine, nonnucleoside reverse transcriptase inhibitors (NNRIs), phenytoin, protease inhibitors, proton pump inhibitors, rifampin, rifabutin. 

Drugs affected by voriconazole include the following benzodiazepines, calcium channel blockers, cisapride, coumarin anticoagulants, cyclosporine, ergot alkaloids, HMG-CoA reductase inhibitors, NNRTIs, phenytoin, protease inhibitors, pimozide, proton pump inhibitors, quinidine, prednisolone, rifabutin, sirolimus, sulfonylureas, tacrolimus, vinca alkaloids. 

Others Acetaminophen, amiodarone, carbamazepine, delavirdine, efavirenz, nevirapine, quinidine, repaglinide, sildenafil, tadalafil, trazodone, vardenafil Amiodarone, amprenavir, atazanavir, ciprofloxacin, cisapride, clarithromycin, diltiozem, erythromycin, fluconazole, fluvoxamine, grapefruit juice (in high ingestion), indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, norfloxacin, ritonavir, telithromycin, troleandomycin, verapamil, voriconazole Carbamazepine, efavirenz, glucocorticoids, macrolide antibiotics, nevirapine, phenytoin, phenobarbital, rifabutin, rifapentine, rifampin, St. John s wort... 

Significant drug interactions include cyclosporins (increased cyclosporine levels), phenytoin, rifampin, and rifabutin (decreased voriconazole levels). Because of its low toxicity profile, this drug may gain importance in the chronic treatment of infections with invasive dimorphic fungi and resistant Candida spp. 

Phenytoin [P] Decreased metabolism of phenytoin with fluconazole and probably voriconazole. 

ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE, VORICONAZOLE CARBAMAZEPINE, PHENYTOIN L plasma concentrations of itraconazole and of its active metabolite, ketoconazole, posaconazole and voriconazole, with risk of therapeutic failure, t phenytoin levels, but clinical significance uncertain. Carbamazepine plasma concentrations are also t These azoles are highly lipophilic, and clearance is heavily dependent upon metabolism by CYP isoenzymes. Phenytoin and carbamazepine are powerful inducers of CYP3A4 and other CYP isoenzymes (CYP2C18/19, CYP1A2) the result is veiy low or undetectable plasma levels. Phenytoin extensively 1AUC of itraconazole by more than 90%. Inhibition of P-gp T bioavailability of carbamazepine Avoid co-administration of posaconazole or voriconazole with carbamazepine. Watch for inadequate therapeutic effects and t dose of itraconazole. Higher doses of itraconazole may not overcome this interaction. Consider the use of less lipophilic fluconazole, which is less dependent on CYP metabolism. Necessaiy to monitor phenytoin and carbamazepine levels... 

Clinically important, potentially hazardous interactions with atazanavir, carbamazepine, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, ritonavir, saquinavir, St John s wort, troleandomycin, voriconazole, warfarin... 

Clinically important, potentially hazardous interactions with alfentanil, alfuzosin, alprazolam, amiodarone, amprenavir, aprepitant, astemizole, atazanavir, bepridil, buprenorphine, bupropion, carbamazepine, chlordiazepoxide, ciclesonide, clozapine, conivaptan, cyclosporine, cyproterone, dasatinib, diazepam, dihydroergotamine, ergot alkaloids, estazolam, eszopidone, etravirine, ezetimibe, fentanyl, fesoterodine, flecainide, flurazepam, fluticasone, halazepam, ivabradine, ixabepilone, ketoconazole, lapatinib, levothyroxine, meperidine, meptazinol, methysergide, midazolam, nifedipine, nilotinib, oral contraceptives, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quazepam, quinidine, ranolazine, rifabutin, rifampin, rifapentine, rimonabant, rivaroxaban, saquinavir, sildenafil, silodosin, simvastatin, solifenacin, St John s wort, tadalafil, temsirolimus, trabectedin, triazolam, vardenafil, voriconazole, zolpidem... 

Coadministration with rifampin, rifabutin, or ritonavir is contraindicated because of accelerated voriconazole metabolism. Efavirenz and perhaps other normucleoside reverse transcriptase inhibitors (NNRTIs) significantly increase voriconazole metabolism and slow the metabolism of the NNRTI. When given with phenytoin, the voriconazole dose should be doubled. Drugs that significantly accumulate in patients receiving voriconazole include cyclosporine,... 

Note also that carbamazepine may reduce the levels of azole antifungals a marked reduction in itraconazole levels has been reported, and some manufacturers of itraconazole consequently say that concurrent use of potent enzyme inducers such as carbamazepine is not recommended. Based on the interaction with phenytoin , (p.552), which results in reduced posaconazole levels, the manufacturer of posaconazole suggests that concurrent use of posaconazole and carbamazepine should be avoided, unless the benefits outweigh the risks. If both drugs are given it would seem sensible to consider increasing the posaconazole dose, and increase monitoring of carbamazepine levels. Based on the interaction with phenytoin , (p.552), the manufacturers of voriconazole also contraindicate the concurrent use of carbamazepine and voriconazole. " ... 

Based on the evidence with phenytoin , (p.552), the manufacturer of voriconazole predicts that phenobarbital will reduce voriconazole levels, and... 

Phenytoin decreases itraconazole and possibly ketoconazole levels (treatment failures seen). Posaconazole and voriconazole are similarly affected. Fluconazole levels are not usually affected by phenytoin, although there is one report of reduced efficacy. 

Studies in healthy subjects found that phenytoin 300 mg daily decreased the maximum serum levels and AUC of voriconazole by 49% and 69%, respectively. Also, voriconazole 400 mg twice daily increased the maximum serum levels and AUC of phenytoin 300 mg daily by 67% and 81%, respectively. ... 

Fluconazole inhibits the cytochrome P450 isoenzymes responsible for phenytoin metabolism (probably CYP2C9). Voriconazole and micona-... 

The interaction between phenytoin and voriconazole is established. The UK manufacturers say that concurrent use of voriconazole and phenytoin should be avoided unless the benefits outweigh the risks. If used together, the manufacturers recommend careful monitoring of phenytoin levels and adverse effects, and doubling the dose of oral voriconazole (from 200 to 400 mg twice daily and from 100 mg to 200 mg twice daily in patients less than 40 kg) or increasing the dose of intravenous voriconazole (from 4 to 5 mg/kg twice daily). 

Purkins L, Wood N, Ghahramani P, Love E Eve MD, F ielding A. Coadministration of voriconazole and phenytoin pharmacokinetic interaction, safety, andtoleraticm. BrJ Clin Pharmacol 2003) 56, 37-44. 

The oral dose of voriconazole does not have to be adjusted in patients who have renal impairment. However, intravenous administration of voriconazole should be avoided in these patients as the carrier vehicle sulfobu-tyl ether P-cyclodextrin sodium can accumulate in these patients. Dosage adjustment is required in patients who have chronic hepatic impairment. As voriconazole is a substrate for a number of cytochrome P450 enzymes, a number of clinically important dmg interactions occur with dmgs including ciclospotin, tacrolimus, phenytoin, warfarin, HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors. 

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