Drug Criteria & Outcomes

Antifungal agents: A bad reputation for drug interactions

By Michele Bryant, PharmD Candidate, Samford University

Advances in drug therapy over the last few decades have revolutionized the management of many common disease states. With these advances, the incidence of polypharmacy, or the concomitant use of multiple medications in a patient, has become a more common occurrence. Unfortunately, this can lead to drug interactions that cause a decrease in the effectiveness of medications or result in adverse drug reactions.

Antifungal agents have been notoriously associated with many drug interactions, but it is difficult to determine which drugs cause clinically significant drug interactions. To help make this process less complicated, the individual classes of antifungal agents can be evaluated based on mechanisms and types of interactions.

Most drug interactions can be characterized as either pharmacodynamic or pharmacokinetic interactions.1 Pharmacodynamic interactions involve additive or antagonistic pharmacologic effects and are usually rapid in onset, although some will present more slowly.2 Pharmacokinetic interactions involve interactions that interfere with four main processes: absorption, distribution, metabolism, and elimination.1 These types of interactions are usually less predictable than pharmacodynamic interactions due to the variability of individual patients.2 The most serious pharmacokinetic interactions with systemic antifungal agents occur by the inhibition and induction of cytochrome P450 (CYP) enzymes, the major enzymes in the liver that metabolize active substances not endogenously produced.1

Azole Antifungal Agents

Typically, the most well known drug interactions with antifungal agents occur with the "azole" antifungal agents. These agents act by inhibiting ergosterol synthesis in the fungal cell membrane by interacting with 14-alpha demethylase, a cytochrome P450 enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane.3 Azole antifungals cause clinically significant drug interactions because they inhibit the elimination of various drugs by competition for the CYP3A4 enzyme, a major enzyme in human cells involved in the hepatic metabolism of many drugs.1 Through this mechanism, the clearance of the affected drugs is decreased and blood concentrations are elevated, meaning that the pharmacological effects of the affected drugs are prolonged and dose-dependent toxicity is increased.1

There are two groups included in the azole antifungal agents: the imidazole group, which includes ketoconazole (Nizoral®), clotrimazole (Mycelex®), and miconazole (Monistat®), and the triazole group, which includes itraconazole (Sporanox®), voriconazole (VFEND®), posaconazole (Noxafil®), and fluconazole (Diflucan®).

Ketoconazole, itraconazole, and voriconazole are strong inhibitors of the CYP3A4 enzyme, with ketoconazole being the strongest, and these agents all show similar drug interaction profiles.1 While blood concentrations of any drug that is heavily metabolized by the CYP3A4 enzyme could potentially be affected by the concomitant use of ketoconazole, itraconazole, or voriconazole, there are some interactions that are more clinically significant.

A life-threatening interaction with these three azoles may occur due the inhibition of the metabolism of dofetilide and quinidine, and the use of these medications concomitantly has been associated with QT prolongation and torsade de pointes.1-3

The use of ketoconazole, itraconazole, and voriconazole with HMG-CoA reductase inhibitors (i.e., statins) that are metabolized through the CYP3A4 enzyme system, which includes simvastatin, lovastatin, and atorvastatin, could substantially increase the risk of developing myopathy, rhabdomyolysis, and acute renal failure.2,3 If no alternative to a short course of treatment with a systemic azole antifungal is available, it is recommended to suspend the statin therapy during treatment with the azole antifungal..2,3 Pravastatin is not metabolized by the CYP3A4 enzyme; therefore, it could be used with patients when longer treatment periods with these drugs are necessary.3

Ketoconazole, itraconazole, and voriconazole also significantly impair the clearance of oxidatively metabolized benzodiazepines, such as alprazolam, midazolam, triazolam, diazepam, and clonazepam.2,3 Lorazepam, oxazepam, and temazepam may be the safest alternatives to use concomitantly with these medications since these drugs are not oxidatively metabolized.2,3

Ketoconazole, itraconazole, and voriconazole used concomitantly with fentanyl (i.e., transdermal patches) can result in respiratory depression, and other analgesics not metabolized by CYP3A4 (e.g., codeine, morphine, tramadol) should be used instead.2

Narrow therapeutic index drugs that may be affected by administration of azole antifungals include digoxin, phenytoin, and warfarin; therefore, close monitoring of these medications should occur during treatment with this group of drugs.1-3

Use of corticosteroids with ketoconazole, itraconazole, and voriconzole can lead to increased plasma concentrations of the steroids, especially methylprednisolone and budesonide, thus amplifying the immunosuppressive and adverse effects of the steroids.2,3 Prednisolone and prednisone pharmacokinetics seem to be less susceptible to CYP3A4 inhibitory interactions with ketoconazole than methylprednisolone.2,3

These azole medications may also interact with the following antiretroviral agents: protease inhibitors, including darunavir plus ritonavir, indinavir, and nelfinavir; and non-nucleoside reverse transcriptase inhibitors, including delaviridine, efavirenz, and nevirapine.3,4 These agents may still be used concomitantly; however, dosage adjustments may need to be made.4

The oral bioavailabilities of these three azoles require an acidic environment for solubility. Histamine-2 (H2) antagonists, proton pump inhibitors, antacids, didanosine (ddI, powder and tablet), which contain acid buffers, have been shown to reduce plasma concentrations of these agents.3 Intraconazole may also inhibit the metabolism of vinca alkaloids resulting in increased or prolonged peripheral neuropathies and ileus.2,3 Similar adverse effects may be seen with the other azole drugs, although this is not as well documented.

The use of voriconazole and long-acting barbiturates is a contraindication, and caution is advised when using voriconazole with short-acting barbiturates as well.2,3

Finally, renal toxicity may be increased with the concomitant use of cyclosporine or tacrolimus and ketoconazole, itraconazole, or voriconazole.1,3

Although miconazole and clotrimazole are in the same class of antifungal agents as ketoconazole, these agents have significantly fewer drug interactions than ketoconazole. However, the uses of miconazole or clotrimazole are mainly limited to topical or vaginal application, thus significant drug interactions are uncommon.

Fluconazole and posaconazole interfere with the CYP3A4 enzymes to a lesser extent than ketoconazole, itraconazole, and voriconazole. In fact, posaconazole has the least amount of drug interactions in the azole class of antifungal agents.2,3 However, fluconazole and fentanyl used concomitantly can result in respiratory depression and terbinafine (Lamisil®) should be considered as an alternative agent.2

Although the life-threatening interactions (i.e., interactions with dofetilide and quinidine) with fluconazole and posaconazole are classified as the same severity level as itraconazole and voriconazole, most other interactions are usually classified as a lower severity level.3 The same common interactions may occur with fluconazole and posaconazole as with the other azoles, but to a lesser degree.

Polyene Antifungal Agents

Polyene antifungals, which include amphotericin B (Amphocin® conventional, AmBisome® liposomal, and nystatin [Mycostatin®] lozenge), work by binding to sterols in the cell membranes of both fungal and human cells. Amphotericin B and nystatin are usually fungistatic in vivo but may have fungicidal activity at high concentrations or against extremely susceptible organisms.3 Most pharmacodynamic interactions caused by antifungal agents are commonly caused by amphotericin B, and the most serious interactions that can occur are nephrotoxic interactions with agents such as antineoplastic agents, aminoglycosides, cyclosporin, salicylates, vancomycin, and zidovudine.1,3

Amphotericin B can also induce hypokalemia that may potentiate the cardiac toxicity of cardiac glycosides (e.g., digoxin), cisapride, and dofetilide, and it may also enhance the curariform effect of neuromuscular blockers.1,3 These phenomena are found to be true with both the conventional and lipid formulations.

Nystatin has poor absorption through the gastrointestinal tract when administered orally; therefore, it is used topically in most cases. There are no significant drug interactions with nystatin when used topically.

Echinocandin Antifungal Agents

The echinocandins are a unique group of antifungal agents, which includes caspofungin (Cancidas®), anidulafungin (Eraxis), and micafungin (Mycamine®). This group of antifungal agents acts by inhibiting the synthesis of a major fungal cell wall component, beta (1,3)-D-glucan, which is not present in mammalian cell walls.3 The echinocandins are administered by intravenous infusion; therefore, many drug interactions that would occur in the gastrointestinal tract are eliminated. The great advantage of this group, however, is that these agents do not inhibit any enzyme in the cytochrome P450 enzyme system; therefore, drug interactions caused by competition of these enzymes should be eliminated.3

Evaluating these agents individually, micafungin was shown to increase the systemic exposure of sirolimus and nifedipine, but the mechanisms of the interactions are not known.2,3 Patients receiving micafungin and either of these agents should be monitored for signs of toxicity, and the nifedipine dosage may need to be reduced.2,3

Micafungin has also caused leukopenia, neutropenia, anemia, and thrombocytopenia; therefore, concomitant use with immunosuppressive agents would warrant the monitoring of patients.

Caspofungin use with cyclosporine could lead to elevated levels of aspartate transaminase (AST) and alanine transaminase (AST).2,3 Drugs that may lead to reduced concentrations of caspofungin include carbamazepine, dexamethasone, efavirenz, phenytoin, fosphenytoin, nelfinavir, nevirapine, or rifampin.3 Caspofungin use with tacrolimus may cause reduced concentrations of tacrolimus.3

Anidulafungin use with cyclosporine resulted in an increased concentration of anidulafungin in clinical studies.3 Also, in clinical studies, no dosage adjustments were needed when anidulafungin was administered with tacrolimus, voriconazole, rifampin, or liposomal amphotericin B.3

Allylamine Antifungal Agents

The allylamine group of antifungal agents, which includes terbinafine and naftifine (Naftin®), interfere with fungal sterol biosynthesis by inhibiting the enzyme squalene monooxygenase, a key enzyme in sterol biosynthesis in fungi. The accumulation of squalene weakens the cell membrane in sensitive fungi. The inhibition of squalene monooxygenase creates a deficiency in ergosterol, a component of fungal membranes necessary for normal growth.3 While terbinafine has a great advantage for systemic use due to its lack of inhibition of the CYP3A4 enzyme, terbinafine has been shown to inhibit the CYP2D6 enzyme. Therefore, terbinafine may inhibit the clearance of drugs that are metabolized by the CYP2D6 enzyme, such as certain beta-blockers (e.g., metoprolol, carvedilol, propranolol), certain antiarrhythmics (e.g., flecainide, propafenone, ecainide), clozapine, codeine, fluoxetine, haloperidol, tricyclic antidepressants, meperidine, and oxycodone.

The general classifications of the interactions with these medications were typically only moderate to low in severity, with the exception of the antiarrhythmic agents flecainide, propafenone, and ecainide, which are classified as more severe.2,3 However, the concomitant use of thioridazine and terbinafine is contraindicated.

The topical use of terbinafine has been shown to be unlikely to have any significant drug interactions.3 Naftifine is used as a topical agent for dermatological use only and is an unlikely cause of any significant drug interactions.3

Miscellaneous Antifungal Agents

The remaining antifungal agents, griseofulvin (Grifulvin® V) and flucytosine (Ancobon®), do not belong to a specific antifungal class. Griseofulvin acts by disrupting the mitotic spindle structure of the fungal cell, which causes an arrest of metaphase of cell division.3 Griseofulvin can decrease the effectiveness of warfarin and oral contraceptives by enhancing the hepatic metabolism of these medications; recommendations include enhanced monitoring of prothrombin time while taking warfarin and using alternate forms of contraception while taking griseofulvin and for one month after the drug is discontinued.1,3

Flucytosine acts by penetrating the fungal cells, where it is deaminated to fluorouracil by the fungal enzyme cytosine deaminase. Acting as an antimetabolite, fluorouracil competes with uracil, interfering with pyrimidine metabolism and eventually disrupting both RNA and protein synthesis of the fungal cell.3 Flucytosine can cause significant hematologic toxicity, and enhanced myelosuppression may occur with antineoplastic agents, especially cytarabine.1,3 Other blood dyscrasia-causing medications, such as clozapine, carbamazepine, and phenothiazines, should be used cautiously with flucytosine.3

Conclusion

Antifungal agents have been implicated in many cases of drug interactions mainly due to the enzymatic inhibition and induction caused by certain agents in this group of medications.1 Although relatively few agents are most problematic, practitioners should use antifungal drugs with extreme caution due to the potential for clinically significant drug interactions.

When considering an antifungal agent, the practitioner must look at each patient case individually. It is imperative to evaluate the other medications that the patient is receiving in anticipation that there may be possible issues with drug interactions.

Each patient may also vary in the metabolism patterns of drugs; therefore, the predictability of a drug interaction in different individual patients may vary.1 Finally, when considering treatment with an antifungal agent or any other antimicrobial agent, one must consider the susceptibility of the presumed pathogen to the antifungal agent.

References

  1. Albengres E, Louet H, Tillement JP. Systemic antifungal agents: Drug interactions of clinical significance. Drug Saf1998;18:83-97.
  2. Hansten PD, Horn JR. Drug Interactions: Analysis and Management. St. Louis, MO: Facts and Comparisons: PM-3, 81-82, 229b-229c, 602a, 607-617, 737a-746, 749-760a, 835-836, 925.
  3. Clinical Pharmacology. Available at: www.clinicalpharmacologyip.com.ezproxy.samford.edu/. Accessed July 12, 2007.
  4. National Institutes of Health. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov. Accessed July 16, 2007.
  5. Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons: 1355-1373j.