Drug interactions of azole antifungals

Fluconazole

Fluconazole is water soluble. It is absorbed rapidly and completely after oral administration with a bioavailability of >90%. Fluconazole has a low protein binding of 11–12%. The elimination half-life [t_1/2] of the drug is 30 hours and the absorption is unaffected by food or gastric acidity. Fluconazole circulates primarily as a free drug. It distributes readily into various body fluids (cerebrospinal fluid and urine) and tissues (liver, kidney, and central nervous system). Most of the drug (60–80%) is eliminated through the renal system where it undergoes glomerular filtration and tubular re-absorption.

Fluconazole has a variable, dose-dependent ability to inhibit CYP3A4 (especially with high daily doses), CYP2C9, and CYP2C19.^[3,5-8]

Itraconazole

Itraconazole is a highly lipophilic drug. Being a weak base (ionized only at a low pH), itraconazole requires gastric acidity for adequate absorption. It should be taken immediately after a full meal for optimal absorption. Achlorhydria retards its absorption. Acidic beverages such as cola may increase its absorption while proton-pump inhibitors, H2-antagonists, and other antacids may retard the same.^[6,9,10]

Itraconazole is highly protein bound (99.8%) and penetrates extensively into human tissues and has a t_1/2 of approximately 30 hours. It is metabolized by the liver (predominantly by the CYP3A4 isoenzyme system) and undergoes enterohepatic recirculation. Hydroxy- itraconazole is the major metabolite which shows an antifungal activity equal to that of the parent compound. Metabolites of itraconazole are excreted in urine and bile.^[3,5,6]

Interaction with statins

Among the statins, atorvastatin, lovastatin, and simvastatin are substrates for CYP3A4. Fluvastatin is a substrate for CYP2C9. Pravastatin and rosuvastatin are excreted primarily in the urine as unchanged drugs.^[7]

Fluconazole, a potent inhibitor of CYP2C9 and CYP2C19, significantly alters the pharmacokinetics of fluvastatin.^[7] Although fluconazole is a weak inhibitor of CYP3A4, there are reports that it can inhibit the metabolism of simvastatin and atorvastatin as well.^[11,12]

As itraconazole is a potent CYP3A4 inhibitor, it significantly alters the pharmacokinetics of lovastatin, simvastatin, and atorvastatin (CYP3A-dependent statins).^[7] The interactions between itraconazole or fluconazole and the statins can produce significant toxicity like rhabdomyolysis. It is a rare, but potentially severe side effect of elevated concentrations of HMG-CoA (3-hydroxy-3methylglutaryl coenzyme A) reductase inhibitors.^[11,12] Therefore, when using itraconazole or fluconazole in patients on HMG-CoA reductase inhibitors, caution should be exercised and switching to alternative statin (pravastatin or rosuvastatin that are not metabolized by CYP3A4) should be considered.^[7]

Interaction with benzodiazepines

Fluconazole and itraconazole inhibit the metabolism of benzodiazepines (mediated by CYP3A4). The interaction between the azoles and benzodiazepines is long lasting, especially with itraconazole. The metabolites of itraconazole play a significant role in the persistence of this interaction.^[13,14] Metabolism of midazolam, triazolam, and diazepam may be inhibited by azoles.^[3,7] The interactions can increase the pharmacodynamic effects of the benzodiazepines causing deep and prolonged sedative effects, prolonged amnesia, and reduced psychomotor performance. Benzodiazepines that are unaffected by concomitant administration of an azole are temazepam, bromazepam, and estazolam.^[7]

Interaction with warfarin

Warfarin is a racemic mixture with R and S-isomers. R-warfarin is mainly metabolized by CYP3A4. 85% of S-warfarin is metabolized by CYP2C9. S-isomer is a more potent (more than 5 times) antagonist of Vitamin K, in comparison to R-isomer.^[15]

Fluconazole will potentiate the anticoagulant effect of warfarin by inhibition of CYP2C9. The interaction between fluconazole and warfarin can occur even if the dose of fluconazole is reduced by 50%. Hence, this combination should be avoided, if possible, as it increases the risk of significant bleeding.^[16] If this is not possible, then the international normalized ratio (INR) must be closely monitored and the dose of warfarin should be adjusted accordingly.^[7] Mootha et al. had reported a case of intraocular hemorrhage following warfarin - fluconazole interaction in a patient with Candida endophthalmitis.^[17]

Since itraconazole is a strong inhibitor of CYP3A4 and has only a limited action on CYP2C9, theoretically it has less effect on the anticoagulant action of warfarin. Despite this, there are reports of itraconazole enhancing the anticoagulant action of warfarin.^[18,19] Patients on warfarin with a high INR are at a greater risk of bleeding, after the introduction of an azole antifungal and need careful monitoring.^[15]

Interaction with calcineurin inhibitors

Conversion of cyclosporine to its metabolites by CYP450 enzymes in the liver and the intestine is the rate limiting step in the elimination of the drug.^[20] A randomized double blind study in renal allograft recipients on cyclosporine showed a slow increase in cyclosporine concentration over a period of 2 weeks, after starting fluconazole at a dose of 200 mg/day.^[21] Fluconazole interacts with cyclosporine and tacrolimus in a dose-dependent manner. Due to the nephrotoxic potential of calcineurin inhibitors, dose reduction, close monitoring of their plasma concentration, and monitoring of renal function are mandatory when patients on cyclosporine or tacrolimus are prescribed more than 200 mg/day of fluconazole.^[22,23] Fluconazole, by inhibiting the P450 enzyme in gut mucosa, inhibits the metabolism of calcineurin inhibitors in gut.^[24] Hence, this interaction depends on the route of administration of the calcineurin inhibitors and is reported to be less with intravenous administration.

Significant interaction occurs between itraconazole and cyclosporine or tacrolimus regardless of the route of administration and hence an adjustment of dose is advised.^[25,26] A dose reduction (of calcineurin inhibitors) protocol of 50% of recommended dose on starting the azole, 70% on day 3 and 75% on day 14 may ensure minimal change in serum levels of tacrolimus.^[27]

Interaction with corticosteroids

Addisonian crisis was reported in a liver transplant recipient, who was on prednisone and fluconazole, after withdrawal of the latter. It was proposed that a reversal of the fluconazole induced suppression of P450 enzymes might have led to an alteration in steroid metabolism.^[28] A hospital based study showed interaction between fluconazole and prednisone, but concluded the interaction to be of little clinical significance at the commonly prescribed doses. However, it is prudent to closely monitor steroid treated patients for any adverse event while introducing or withdrawing fluconazole.^[29]

Itraconazole increases the plasma concentration of oral and intravenous methylprednisolone by inhibiting CYP3A4 mediated metabolism and by inhibition of P-glycoprotein mediated elimination. These in turn decrease the morning plasma cortisol level.^[30-32]

Simultaneous administration of itraconazole and intravenous dexamethasone is reported to reduce the systemic clearance of the latter, thus enhancing it’s adrenal suppressant effect.^[33] Prednisolone shows only minor interaction with itraconazole which is of limited clinical significance. Hence, prednisolone should be the preferred steroid in combination with the azole antifungals.^[32,34]

Metabolism of inhaled steroids such as budesonide and fluticasone is also inhibited by itraconazole resulting in suppression of morning plasma cortisol levels.^[7]

Interaction with phenytoin

Azoles can interact with phenytoin in a bidirectional manner - azole first inhibits the CYP mediated metabolism of phenytoin, which is followed by the phenytoin induced CYP mediated metabolism of azoles.^[7] There are case reports of fluconazole induced symptomatic phenytoin toxicity in patients on high doses (400 mg/day) of the former.^[35,36] Data from a placebo controlled randomized study on healthy volunteers showed a significant increase in phenytoin concentration after simultaneous administration of fluconazole (200 mg/day for 14 days).^[37] Patients receiving phenytoin or carbamazepine have shown treatment failure or relapse of fungal infections, when treated with azoles due to the phenytoin/carbamazepine induced metabolism of azoles.^[3,38]

Interactions that decrease the systemic absorption of azoles

The azoles are weak bases and at higher pH, they dissolve more slowly.^[7] H2-receptor antagonists, proton pump inhibitors and antacids reduce the absorption of itraconazole.^[9,39,40] Absorption of fluconazole is unaffected by gastric pH.^[7]

Co-administration of drugs such as phenytoin, phenobarbital, carbamazepine, rifampicin, isoniazid, ritonavir, efavirenz, and other inducers of CYP3A4 can induce the metabolism of azole antifungals. This in turn can result in failure of antifungal treatment.^[3,7]

Table 1 shows the less commonly encountered drug interactions of azoles.