Clinical use of the antifungal azoles is problematic in some patients because of the potential for interactions with coad- ministered drugs [32, 66, 102–113]. Thus a patient’s concom- itant medications should be carefully reviewed for potential
67 Azoles
drug interactions prior to start and discontinuation of triazole therapy. These interactions can be broadly categorized in two major types: those that result in decreased or, less commonly, increased serum concentrations of the azoles, and those inter- actions in which the azoles produce increased plasma con- centrations and/or clinical effect of another agent. Because several of the interactions pose sufficient risk, coadministra- tion is not recommended. Specific interactions reported with individual azoles are provided in Table 2.
The most commonly encountered interaction is due to a CYP450 interaction resulting in an increase in the concentra- tion of the coadministered medication [105, 114]. Each of the triazoles is a substrate for one or more of the CYP450 isoen- zymes; however, the individual triazoles vary in their affinity for the various enzymes [115]. This interaction includes flu- conazole and posaconazole, which are not significantly metabolized by the CYP450 enzymes but are substrates for the inhibition of CYP450 isoenzymes. Fluconazole is an inhibitor of CYP3A4, CYP2C9, and CYP2C19 [103]. The following drugs should not be administered with fluconazole due to risk of QT prolongation: astemizole, bepridil, cisap- ride, levomethadyl, mesoridazine, pimozide, ranolazine, terfenadine, thioridazine, or ziprasidone. Fluconazole also increases serum levels of ergot alkaloids, and concomitant use is contraindicated due to risk of toxicity.
Itraconazole is both a substrate and an inhibitor of the CYP450 enzymes, specifically CYP3A4 and CYP2C9 [103].
Itraconazole is the most potent triazole inhibitor of CYP3A4.
Coadministration of itraconazole with cisapride, dofetilide, pimozide, terfenadine, levacetylmethadol, or quinidine results in elevated concentrations of these drugs and is con- traindicated due to risk of QT prolongation, torsades de pointes, and ventricular arrhythmia [116, 117]. Lovastatin, simvastatin, oral midazolam, triazolam, and ergot alkaloid clearance are also markedly reduced, and coadministration is contraindicated [118]. Itraconazole may expose patients to higher levels of vinca alkaloids, and concomitant use of itra- conazole and vincristine in patients with leukemia or lym- phoma was associated with increased risk of neurotoxicity, including severe myalgias, arthralgias, paralysis, and para- lytic ileus [119, 120].
Voriconazole is both a substrate and an inhibitor of the CYP450 enzymes, specifically CYP2C19, CYP2C9, and CYP3A4 [70, 114, 121]. Similar to the other triazoles, coad- ministration of voriconazole with astemizole, cisapride, pimozide, quinidine, or terfenadine is contraindicated due to risk of QT prolongation and torsades de pointes. Voriconazole can also substantially increase serum levels of ergot alka- loids, and concomitant use is not recommended.
Although posaconazole is not extensively metabolized by CYP450 enzyme system, it is an inhibitor of the CYP450 3A4 isoenzyme and has the capacity for drug-drug interactions
through this mechanism. Posaconazole is not a major substrate or inhibitor of other isoenzymes, including CYP2C8/9, CYP1A2, CYP2D6, or CYP2E1 [122]. In patients taking posaconazole, contraindicated drugs include astemizole, cisapride, dihydroergotamine, ergoloid mesylates, ergonovine, ergotamine, halofantrine, methylergonovine, methysergide, pimozide, quinidine, and terfenadine.
Other CYP450 interactions due to this class of interac- tions are common but can often be managed by monitoring and dose adjustment of the coadministered medication. For example, interaction with the calcineurin inhibitors in the transplant population is common to all of the triazoles to some degree. Similarly, interaction with warfarin requires enhanced monitoring of the degree of anticoagulation when administered with the azole class of drugs.
Drug interactions that result in decreased concentrations of the azole occur via two primary mechanisms. In the first type, solubilization and subsequent absorption of weakly basic, highly lipophilic azoles is impaired by agents that decrease gastric acidity. The agents affected are ketocon- azole, itraconazole capsules, and posaconazole. In situations where ketoconazole, itraconazole capsules, or posaconazole is used in patients receiving antisecretory therapy, adminis- tration of the azole with an acidic beverage, e.g., Classic Coca-Cola® or Pepsi®, is recommended [29, 36, 123].
The second mechanism by which serum concentrations of the azole are reduced is via induction or inhibition of azole metabolism by agents that impact hepatic cytochrome P-450 activity [103, 105, 114]. All azoles are affected, although clinical significance of these interactions is least with flucon- azole since hepatic metabolism plays only a minor role in clearance of this drug. In contrast, the impact on other agents is substantial and therapeutic failures are possible in patients receiving the other azoles with enzyme-inducing agents [105, 124–129]. Whenever possible, concomitant therapy with azoles and these inducing agents, including phenytoin, carbamezapine, and rifampin, should be avoided [130].
Another mechanism, via which antifungal azoles may increase plasma concentrations and/or the effect of coadmin- istered agents, involves inhibition of P-glycoprotein, an ATP-dependent plasma membrane transporter involved in intestinal absorption, brain penetration, and renal secretion of a number of chemically diverse agents [131]. Of the avail- able azoles, itraconazole, ketoconazole, and posaconazole have the highest potential to interact with P-glycoprotein.
Inhibition of this transporter is thought to be the primary mechanism by which itraconazole enhances the neurotoxic- ity of vincristine [119, 120, 132, 133] and decreases renal clearance (increases serum concentration) of digoxin [115, 134, 135]. Further investigation is necessary to determine the extent to which the newer triazole derivatives interact with P-glycoprotein.
Table 2Drug interactions involving antifungal azoles Effect of interactionFluconazoleItraconazoleVoriconazolePosaconazole Decreased absorption of azolesAntacids- aluminum carbonate (basic), aluminum hydroxide, aluminum phosphate, calcium, dihydroxyaluminum aminoacetate, dihydroxyaluminum sodium carbonate, magaldrate, magne- sium carbonate, magnesium hydroxide, magnesium trisilicate, sodium bicarbonate
H2-blockers-cimetidine Proton pump inhibitors- esomeprazole, lansopra- zole, omeprazole, pantoprazole, rabeprazole H2-blockers-cimetidine, famotidine, nizatidine, ranitidine, roxatidine Proton pump inhibitors-esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Decreased plasma concentration of azole due to metabolism
Antibiotics- rifampin, rifapentineAntibiotics-isoniazid, rifabutin, rifampin, rifapentineAntibiotics- rifabutin, rifampin, rifapentineAntibiotics-rifabutin, rifampin, rifapentine Antiepileptics-carbamazepine, fosphenytoin, phenytoinAntiepileptics-carbamazepine, fosphenytoin, phenytoinAntiepileptics-phenytoin Antiretrovirals-darunavir, didanosine, efavirenz, etravirine, nevirapine Barbiturates-phenobarbital
Antiretrovirals-amprenavir, darunavir, delavirdine, efavirenz, nevirapine, ritonavir, tipranavir Barbiturates-alfuzosin, aprobarbital, butabarbital, eterobarb, heptabarbital, hexobarbital, mephobarbital, pentobarbital, phenobarbital, secobarbital Increased plasma concentration of azole due to coadministered drug
Antibiotics-clarithromycin Antiretrovirals-amprenavir, darunavir, fosamprenavir, lopinavir, ritonavir
Antiretrovirals-delavirdine, etravirine, fosamprenavir, nelfinavir, nevirapine, saquina- vir, tipranavir Oral contraceptives- ethinyl estradiol, norethindrone Proton pump inhibitor – omeprazole Increased plasma concentration of coadministered drug
Aldosterone antagonists-eplerenone Anesthetics-enflurane, halothane, isoflurane Antianginal-ranolazine Antiarrhythmics-acecainide, ajmaline, amiodarone, aprindine, azimilide, brety- lium, disopyramide, flecainide, hydroquini- dine, ibutilide, lorcainide, pirmenol, prajmaline, procainamide, propafenone quinidine, sematilide, sotalol, tedisamil Aldosterone antagonists-eplerenone Alpha-adrenergic blocker-alfuzosin Antianginal- ranolazine Antiarrhythmics-digoxin, disopyramide, dofetilide, quinidine Antibiotics-clarithromycin, erythromycin, telithromycin, trimetrexate Anticholingergic-oxybutynin Alpha-adrenergic blockers- alfuzosin Antianginal-ranolazine Antiarrhythmics-quinidine Antibiotics-clarithromycin, erythromycin, rifabutin Anticoagulants-acenocoumarol, dicumarol, phenprocoumon, warfarin Antiarrhythmics-quinidine Antibiotics- rifabutin Antiepileptics-phenytoin Antimalarials-halofantrine Antipsychotics-pimozide Antiretrovirals-etravirine Antihistamine-astemizole(off market), terfenadine (off market)
Antibiotics-clarithromycin, erythromycin, gemifloxacin, levofloxacin, nitrofurantoin, rifabutin, spiramycin, sulfamethoxazole, telithromycin, trimethoprim, trimetrexate(?) Anticoagulants- acenocoumarol, anisindione, dicumarol, phenindione, phenprocoumon, warfarin Antidepressants-amitriptyline, amoxapine, desipramine, dibenzepin, doxepin, fluoxetine, imipramine, nortriptyline, trimipramine Antiemetic-dolasetron, droperidol, prochlorperazine Antiepileptics-carbamazepine, fosphenytoin, phenytoin Antihistamines- astemizole, terfenadine Antimalarials-chloroquine, halofantrine, mefloquine Antineoplastic agents-arsenic trioxide, ixabepilone, tretinoin Antiprotozoal-pentamidine Antipsychotics-amisulpride, chlorpromazine, haloperidol, mesoridazine, pimozide, quetiapine, risperidone, sertindole, sultopride, thioridazine, trifluoperazine, ziprasidone, zotepine Antiretrovirals-atevirdine, etravirine, nevirapine, tipranavir, zidovudine Antiviral-foscarnet Benzodiazepines-alprazolam, midazolam, triazolam Calcium channel blockers-amlodipine, bepridil, felodipine, isradipine, lidoflazine, nicardipine, nifedipine
Anticoagulants- acenocoumarol, anisindione, dicumarol, phenindione, phenprocou- mon, warfarin Antidepressants-buspirone, trazodone Antidiarrheal agents-loperamide Antiemetic-aprepitant Antihistamines-astemizole, terfenadine Antimalarials-halofantrine Antineoplastic agents-bexarotene, busulfan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, nilotinib, sunitinib, vinblastine, vincamine, vincristine, vincristine liposome, vindesine, vinorelbine Antiparasitic-praziquantel Antipsychotics-aripiprazole, pimozide, quetiapine, risperidone Antiretrovirals- amprenavir, darunavir, etravirine, fosamprenavir, indinavir, maraviroc, saquinavir Benzodiazepines- alprazolam, diazepam, midazolam, triazolam Calcium channel blockers-amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, verapamil Calcimimetic-cinacalcet Calcitriol analog- paricalcitol Corticosteroids- betamethasone, budesonide, corticotropin, cosyntropin, deflazacort, dexamethasone, fludrocortisone, fluocortolone, hydrocortisone, methyl- prednisolone, paramethasone, predniso- lone, prednisone, triamcinolone Endothelin receptor antagonists-ambrisentan, bosentan Ergot alkaloids- dihydroergotamine, ergoloid mesylates, ergonovine, ergotamine, methylergonovine, methysergide Glucose lowering agents-repaglinide Immunosuppressants-cyclosporine, sirolimus, tacrolimus, temsirolimus Lipid-lowering agents- atorvastatin, cerivastatin, lovastatin, rosuvastatin, simvistatin Muscarinic receptor antagonist-darifenacin Antiepileptics-fosphenytoin, phenytoin Antineoplastic agents-erlotinib, imatinib, ixabepilone, lapatinib, nilotinib, vinblastine, vincris- tine, vincristine liposome, vinorelbine, sunitinib, temsiroli- mus, tretinoin Antipsychotics-pimozide Antiretrovirals-amprenavir, atazanavir, delavirdine, efavirenz, etravirine, fosampre- navir, maraviroc, nelfinavir, nevirapine, saquinavir, tipranavir Antihistamines- astemizole, terfenadine Benzodiazepines-alprazolam, midazolam, triazolam Calcium channel blockers-amlo- dipine, diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine, nitrendipine, verapamil Calcimimetic-cinacalcet Calcitriol analog-paricalcitol Ergot alkaloids-dihydroergotamine, ergoloid mesylates, ergonovine, ergotamine, methylergonovine, methysergide Proton pump inhibitors- esomeprazole, omeprazole Immunosuppressants-cyclosporine, sirolimus, tacrolimus Opiods- alfentanil, methadone
Antiarrhythmics-quinidine Antibiotics- rifabutin Antiepileptics-phenytoin Antimalarials-halofantrine Antipsychotics-pimozide Antiretrovirals-etravirine Antihistamine- astemizole(off market), terfenadine (off market) Benzodiazepines-midazolam Calcium channel blockers- amlodipine, diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine, nitrendipine, verapamil Ergot alkaloids- dihydroergotamine, ergoloid mesylates, ergonovine, ergotamine, methylergonovine, methysergide Immunosuppressants- cyclosporine, sirolimus, tacrolimus Serotonic receptor antago- nists-cisapride (off market) Statins-atorvastatin, lovastatin, simvistatin (continued)
Effect of interactionFluconazoleItraconazoleVoriconazolePosaconazole Corticosteroids-prednisone COX2-inhibitors-celecoxib, valdecoxib Endothelin receptor antagonist-bosentan Ergot alkaloids- dihydroergotamine, ergoloid mesylates, ergonovine, ergotamine, methylergonovine, methysergide Immunosuppressants-cyclosporine, sirolimus, tacrolimus Lipid-lowering agents- atorvastatin, cerivasta- tin, fluvastatin, lovastatin, probucol, rosuvastatin, simvistatin Melatonin receptor agonists- ramelteon Opiods- alfentanil, fentanyl, levomethadyl, methadone Oral contraceptives- ethinyl estradiol, etonogestrel, levonorgestrel, mestranol, norelgestromin, norethindrone, norgestrel Peptides-octreotide, vasopressin Sedatives-chloral hydrate Serotonic receptor antagonists-cisapride Sulfonylureas-glimepiride, glipizide, glyburide, tolbutamide Triptans-eletriptan, zolmitriptan Opiods- alfentanil, fentanyl, levomethadyl, mifepristone Oral contraceptives and hormonal replace- ment-estrogens, estradiol, estriol, estrone, estropipate, eszopiclone Phosphodiesterase inhibitors- cilostazol, sildenafil, tadalafil, vardenafil Serotonic receptor antagonists-cisapride Stimulants-modafinil Triptans- almotriptan, eletriptan Vasopressin receptor antagonists-conivaptan
Oral contraceptives- ethinyl estradiol, norethindrone Serotonic receptor antagonists- cisapride Statins-atorvastatin, cerivastatin, lovastatin, simvistatin Sulfonylureas-glipizide, glyburide, tolbutamide Triptans-eletriptan Vinca alkaloids-vinblastine, vincristine, vincristine liposome, vinorelbine
Table 2(continued)
71 Azoles