Important Drug Interactions for the Antifungal Drug Itraconazole

Patients taking the oral antifungal drug itraconazole (SPORANOX, TOLSURA) should be aware that it has clinically important interactions with many other prescription medications that can affect the safety or effectiveness of itraconazole or the interacting drugs.

Oral itraconazole was originally approved by the Food and Drug Administration (FDA) in 1992 to treat certain serious fungal infections involving the lungs or other internal organs.[1] In 1995, it was approved for fungal toenail infections, a condition known as onychomycosis.

For 20 years, Public Citizen’s Health Research Group has recommended against using itraconazole for treatment of fungal nail infections because the drug has serious, potentially fatal risks — including risks of heart failure, abnormal heart rhythms and liver failure — that far outweigh the benefit of treating a minor cosmetic condition.[2] Itraconazole should be used only to treat serious fungal infections.

Notably, the labeling for itraconazole includes a black-box warning — the strongest warning that the FDA can require — that lists more than two dozen drugs that should never be taken in combination with itraconazole because the risk of life-threatening drug interactions is so great.[3]

Increased risk of fatal heart rhythm abnormalities[4],[5],[6]

Like some other drugs in the azole family of antifungal drugs, itraconazole can cause prolongation of the QT interval. QT prolongation is a change in the electrical activity of the heart that can lead to a fatal heart rhythm disturbance called torsades de pointes, which can cause cardiac arrest and sudden death.

Numerous oral drugs, when used concomitantly (at the same time) with itraconazole, further increase the risk of QT prolongation (see Table 1, below, for examples). The list of such drugs includes certain medications for treating abnormal heart rhythms, Alzheimer’s disease, bacterial infections, depression, HIV infection, opioid withdrawal and psychosis, among others.

In most cases, these interacting drugs themselves also cause QT prolongation beyond that caused by itraconazole alone. In addition, itraconazole can inhibit substances in the liver called enzymes that metabolize (break down or chemically modify) many of these same interacting drugs, thus increasing the blood levels of the interacting drugs and further exacerbating the risk of QT prolongation. Importantly, the liver-enzyme–inhibiting effects of itraconazole can persist for up to two weeks after stopping the drug because it takes a long time for the drug to be cleared from the body. Therefore, the risk of these adverse drug interactions can persist for up to two weeks after itraconazole treatment has been discontinued.

For several of these drugs, the risk of QT prolongation and potentially fatal abnormal heart rhythms is so high that they should not be taken concomitantly with itraconazole or for two weeks after itraconazole treatment has been discontinued.

Table 1: Examples of Oral Drugs That May Increase the Risk of QT Prolongation and Potentially Fatal Heart Rhythm Abnormalities

†Brand-name combination products were excluded.
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use by Worst Pills, Best Pills News

Other important drug interactions[7],[8],[9]

Itraconazole can inhibit liver enzymes involved in the breakdown of many other drugs. As a result, concomitant use of itraconazole and these drugs can increase the blood levels of the other drugs to potentially toxic levels (see Table 2, below, for examples). Again, for many of these interacting drugs, the risk of drug toxicity is so great that they should not be taken concomitantly with itraconazole or for two weeks after itraconazole treatment has been discontinued.

Table 2: Examples of Other Oral Drugs That May Reach Toxic Levels When Taken Concomitantly With Itraconazole

†Brand-name combination products were excluded.
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use Except for Panic Disorder by Worst Pills, Best Pills News
***Designated as Do Not Use by Worst Pills, Best Pills News

The following are some particularly notable examples of such drug interactions.

Cholesterol-lowering statins

Concomitant use of itraconazole with certain statin drugs, such as simvastatin (FLOLIPID, ZOCOR), can increase the blood levels of these statin drugs, thereby increasing the risk of statin-induced myopathy (muscle damage). In severe cases, this condition can progress to rhabdomyolysis, a life-threatening, muscle-destroying condition that can lead to sudden kidney failure and death. Patients taking certain statin drugs who are prescribed itraconazole may need to temporarily discontinue the statin, take a lower statin dose or switch to a different cholesterol-lowering treatment until two weeks after completion of the itraconazole treatment.

Digoxin (LANOXIN)

Concomitant use of itraconazole and digoxin — which is used to treat heart failure and to control heart rate in patients with atrial fibrillation (a common abnormal heart rhythm characterized by an irregular and often rapid heartbeat) — can result in increased and potentially highly toxic blood levels of digoxin. Common symptoms of digoxin toxicity are loss of appetite, nausea, vomiting and fatigue. Digoxin toxicity can lead to abnormal heart rhythms. If concomitant use of itraconazole and digoxin is unavoidable, digoxin dosage usually should be reduced and more frequent monitoring of blood digoxin levels should occur, especially during initiation and discontinuation of itraconazole.

Warfarin (COUMADIN, JANTOVEN)

Concomitant use of itraconazole and the anticoagulant (blood thinner) warfarin can increase blood levels of warfarin, which can increase the risk of bleeding complications. Ideally, concomitant use of these two drugs should be avoided. If such use is unavoidable, more frequent monitoring of warfarin levels should occur during initiation and discontinuation of itraconazole.

What You Can Do

If you need treatment with itraconazole, review all your other medications with your doctor to assess for potentially significant drug interactions. If you are taking a medication that interacts with itraconazole, you may need to adjust the dosage of the interacting drug, undergo more frequent monitoring of the blood levels of the interacting drug or stop the interacting drug, or your doctor may advise you to take a different drug for your fungal infection. Be aware that other drugs not listed in this article also may have dangerous interactions with itraconazole.
 

References

[1] Food and Drug Administration. Approval package for NDA 020694. 1996. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020694ap.pdf. Accessed September 6, 2021. PDF page 12.

[2] Worst Pills, Best Pills. Drug profile: itraconazole and terbinafine. April 30, 2021. https://worstpills.org/member/drugprofile.cfm?m_id=279. Accessed September 6, 2021.

[3] Janssen Pharmaceutical Companies. Label: itraconazole (SPORANOX). March 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020083s063lbl.pdf. Accessed September 6, 2021.

[4] Ibid.

[5] Mayne Pharma Inc. Label: itraconazole (TOLSURA). June 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=306352d1-9d5a-49ad-b72d-893b99546861&type=display. Accessed September 6, 2021.

[6] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “itraconazole.” Accessed September 6, 2021.

[7] Janssen Pharmaceutical Companies. Label: itraconazole (SPORANOX). March 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020083s063lbl.pdf. Accessed September 6, 2021.

[8] Mayne Pharma Inc. Label: itraconazole (TOLSURA). June 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=306352d1-9d5a-49ad-b72d-893b99546861&type=display. Accessed September 6, 2021.

[9] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “itraconazole.” Accessed September 6, 2021.