In the public openFDA FAERS extract (20,328,575 total reports, export dated June 8, 2026), azole antifungals (any-role named, 1986–2026) account for 151,266 reports — 77.3 percent serious and 17.1 percent (25,827) with a fatal outcome — led by fluconazole (59,511 reports), voriconazole (24,232), ketoconazole (13,404), posaconazole (12,529) and itraconazole (10,827); drug interaction is the #3 reaction (8,003) reflecting CYP450 inhibition, and the indication profile is dominated by oncology/transplant prophylaxis (antifungal prophylaxis, AML, plasma-cell myeloma, aspergillosis).
This article provides a class-level descriptive read of systemic and topical azole antifungal reporting in the FDA Adverse Event Reporting System (FAERS). It is written for clinical pharmacists, infectious-disease specialists, oncology/transplant formulary managers, and pharmacovigilance teams who evaluate these numbers in clinical risk assessment, prior-authorization design, and therapeutic monitoring guidelines. Every figure here is computed from the public openFDA FAERS extract. It is not a disproportionality signal analysis, it is not a safety claim, and it is not incidence data. FAERS is a spontaneous-reporting system: it captures what was reported, never what was caused, and it has no exposure denominator. For the class-wide FAERS methodology and the database aggregate picture, see the companion inside 20 million FAERS reports; for adjacent class cuts, see fluoroquinolone antibiotic adverse events by the numbers and proton pump inhibitor adverse events by the numbers. For access and shortage context, see Bicillin LA shortage and importation.
Methodology, in one paragraph
A report is counted for the class when an azole antifungal substance name appears anywhere in that report's drug list — as a suspect, concomitant, or interacting drug — using a substring match across the drug_substances, drug_generics, and drug_brands fields (so "fluconazole" and "isavuconazonium sulfate" both count). We explicitly exclude benzimidazole proton pump inhibitors (such as omeprazole and pantoprazole, which contain the "azole" string but are pharmacologically unrelated). Because a single report can name several drugs, the per-molecule totals sum to more than the 151,266 class-level (union, deduplicated) reports. A "serious" report is any report the FDA coded as serious. A report counts toward death when the seriousness field carries a death flag or the outcome field carries a Fatal outcome. Reactions are coded to MedDRA Preferred Terms and case-normalized. FAERS does not link a reaction to a specific drug within a multi-drug report, so the reaction counts below are report-level for reports that name an azole antifungal — they are not proof that the drug caused the event. This "any role" convention is intentionally inclusive and matches the other class cuts in this series; it will exceed suspect-only counts cited elsewhere.
How many FAERS reports name an azole antifungal, and why is the fatality share so high (17.1%)?
The azole antifungal class has a distinct and complex footprint in the history of the FDA Adverse Event Reporting System. Across all reporting years, the deduplicated union of reports naming at least one azole antifungal drug is 151,266.
To put this in perspective, this class cut is smaller than widely used cardiovascular classes in our pharmacovigilance series, such as DOAC adverse events by the numbers (~250,000 reports), but is comparable in size to anti-infective classes like fluoroquinolone antibiotic adverse events by the numbers. However, the outcome distribution within this cohort is uniquely severe:
| Measure | Value | Share of Class |
|---|---|---|
| Total reports (any role) | 151,266 | 100.0% |
| Serious | 116,884 | 77.3% |
| Death flag or fatal outcome | 25,827 | 17.1% |
| Female patients | 71,976 | 47.6% |
| Male patients | 63,243 | 41.8% |
| Unknown patient sex | 16,047 | 10.6% |
At 17.1 percent, the fatality rate in the azole antifungal cohort is the highest among all the drug classes analyzed in our series. For comparison, the fatality rate for corticosteroids is 11.5 percent, and for beta-blockers, it is 10.1 percent.
This extremely high mortality share must not be misinterpreted as a sign of drug-induced lethality. Azole antifungals are primarily prescribed in systemic formulations (like voriconazole, posaconazole, and isavuconazole) to treat or prevent invasive fungal infections (such as invasive aspergillosis, candidiasis, and mucormycosis) in highly vulnerable, immunocompromised populations. These include patients undergoing active chemotherapy for acute myeloid leukemia (AML), bone marrow transplant recipients, and advanced HIV/AIDS patients. In these clinical cohorts, the baseline mortality rate is exceptionally high due to the underlying diseases and the opportunistic infections themselves. Thus, the 17.1 percent fatality rate is a reflection of the high-acuity population receiving these therapies, where death is a frequent clinical outcome, rather than a toxicological properties of the azole molecules.
The reporter mix within the azole dataset confirms its clinical nature:
| Reporter Type | Reports | Share of Class |
|---|---|---|
| Other healthcare professionals | 45,687 | 30.2% |
| Physicians | 45,427 | 30.0% |
| Consumers | 40,565 | 26.8% |
| Pharmacists | 11,554 | 7.6% |
| Unknown reporters | 6,644 | 4.4% |
| Lawyers | 1,389 | 0.9% |
With physicians, pharmacists, and other healthcare professionals accounting for nearly 68 percent of all submissions, the azole safety profile in FAERS is heavily driven by clinical reports. Lawyer-filed reports represent a negligible 0.9 percent (1,389 reports), demonstrating that this registry represents spontaneous, clinical-use pharmacovigilance rather than litigation-driven data.
Which azole concentrates the most reports — fluconazole, voriconazole, posaconazole, isavuconazole?
Looking at individual substances reveals a clear hierarchy. Because azoles are used in both systemic (oral/IV) and topical formulations, the substance list includes a wide range of indications.
The table below details the top substances identified within the azole cohort:
| Substance | Reports | Share of Class | Primary Indication Profile |
|---|---|---|---|
| Fluconazole | 59,511 | 39.3% | Candidiasis, Cryptococcal Meningitis, Prophylaxis |
| Voriconazole | 24,232 | 16.0% | Invasive Aspergillosis, Candidemia, Prophylaxis |
| Ketoconazole | 13,404 | 8.9% | Cushing's Syndrome (Systemic), Topical Fungal Infections |
| Posaconazole | 12,529 | 8.3% | Prophylaxis in AML/MDS, Invasive Aspergillosis |
| Itraconazole | 10,827 | 7.2% | Histoplasmosis, Blastomycosis, Onychomycosis |
| Clotrimazole | 10,748 | 7.1% | Vulvovaginal Candidiasis, Oral Thrush (Topical) |
| Miconazole nitrate | 5,021 | 3.3% | Topical/Vaginal Fungal Infections |
| Isavuconazonium sulfate | 3,065 | 2.0% | Invasive Aspergillosis, Mucormycosis |
| Miconazole | 1,660 | 1.1% | Topical Antifungal |
| Tioconazole | 1,497 | 1.0% | Vulvovaginal Candidiasis (OTC) |
| Econazole nitrate | 778 | 0.5% | Tinea Pedis, Tinea Cruris (Topical) |
| Terconazole | 387 | 0.3% | Vulvovaginal Candidiasis |
| Oxiconazole nitrate | 128 | 0.1% | Topical Antifungal |
| Sertaconazole nitrate | 77 | 0.1% | Tinea Pedis (Topical) |
| Oteseconazole | 26 | <0.1% | Recurrent Vulvovaginal Candidiasis |
Note: Reports sum to more than the class-level union because a single patient report may list multiple azoles concurrently.
Fluconazole is the dominant agent, representing 39.3 percent of the class. This is driven by its position as a primary therapeutic option for mucosal candidiasis and its extensive use in both outpatient vaginal candidiasis and inpatient prophylaxis. Voriconazole is the second most reported, reflecting its status as the primary therapy for invasive aspergillosis.
Ketoconazole represents 8.9 percent of reports. Systemic ketoconazole carries severe boxed warnings for hepatotoxicity and adrenal insufficiency, which led to a major restriction of its oral use by the FDA. However, topical formulations (shampoos, creams) remain widely used and contribute significantly to the substance count. Isavuconazonium sulfate (3,065 reports) is a newer, high-acuity agent approved for invasive aspergillosis and mucormycosis. Its low report volume is a function of its niche market share and more recent approval timeline.
Clinical Pharmacology: Imidazoles vs. Triazoles
To clinically evaluate the FAERS safety data, we must distinguish between the two primary chemical classes within the azole family:
Imidazoles
Imidazoles, including ketoconazole (13,404 reports), miconazole (combined: 6,681 reports), and clotrimazole (10,748 reports), contain a five-membered ring with two nitrogen atoms. Because imidazoles exhibit lower selectivity for fungal cytochrome P450 enzymes compared to mammalian enzymes, they are associated with a higher rate of systemic toxicity. Systemic ketoconazole, for example, potently inhibits mammalian steroidogenesis, leading to adrenal insufficiency and decreased testosterone production. Consequently, the clinical use of imidazoles is now primarily restricted to topical administrations, where systemic absorption is minimal.
Triazoles
Triazoles, such as fluconazole (59,511 reports), voriconazole (24,232 reports), posaconazole (12,529 reports), and isavuconazole (3,065 reports), contain a five-membered ring with three nitrogen atoms. Triazoles exhibit a much higher affinity for fungal 14-alpha-demethylase than for human CYP450 enzymes, resulting in a improved safety profile for systemic administration. This chemical class forms the basis of modern systemic antifungal therapy.
What are the top reported reactions, and do they match the labeled class profile?
Analyzing the top 20 reported reactions in the azole cohort reveals the prominent role of drug interactions and clinical complications:
| MedDRA Preferred Term | Reports | Share of Class | Clinical Context & Interpretation |
|---|---|---|---|
| Drug ineffective | 13,866 | 9.2% | Widespread in invasive fungal infections due to resistance or subtherapeutic drug levels. |
| Off label use | 9,675 | 6.4% | Reflects off-label prophylactic dosing and unapproved indications in pediatric populations. |
| Drug interaction | 8,003 | 5.3% | Core pharmacological safety concern; driven by CYP3A4 inhibition. |
| Diarrhoea | 5,585 | 3.7% | Common gastrointestinal side effect of oral formulations. |
| Death | 5,276 | 3.5% | Captured as a reaction term in severe oncology/transplant cases. |
| Pyrexia | 5,126 | 3.4% | Sign of underlying infection or drug fever. |
| Nausea | 5,048 | 3.3% | Common gastrointestinal adverse event. |
| Fatigue | 4,686 | 3.1% | Non-specific systemic symptom. |
| Condition aggravated | 4,485 | 3.0% | Progression of underlying severe fungal or malignant disease. |
| Pneumonia | 4,433 | 2.9% | Concomitant pulmonary infection in immunocompromised hosts. |
| Dyspnoea | 4,195 | 2.8% | Pulmonary distress related to pneumonia or fluid overload. |
| Febrile neutropenia | 4,061 | 2.7% | Underlying oncology disease/chemotherapy complication. |
| Rash | 3,656 | 2.4% | Hypersensitivity reaction; common with voriconazole (photosensitivity). |
| Headache | 3,499 | 2.3% | Common transient side effect. |
| Product use in unapproved indication | 3,464 | 2.3% | Widespread pediatric and niche off-label clinical use. |
| Acute kidney injury | 3,131 | 2.1% | Driven by concomitant nephrotoxic drugs (e.g., cyclosporine, tacrolimus, amphotericin B). |
| Asthenia | 3,051 | 2.0% | Systemic weakness. |
| Pain | 3,034 | 2.0% | General somatic complaint. |
| Neutropenia | 2,967 | 2.0% | Chemotherapy-induced or drug-induced hematologic toxicity. |
| Anaemia | 2,949 | 1.9% | Underlying hematologic malignancy or chronic disease. |
The third most common reaction is Drug interaction (8,003 reports, 5.3 percent of the class). Azole antifungals are potent inhibitors of the cytochrome P450 (CYP450) enzyme system, particularly CYP3A4, CYP2C9, and CYP2C19. Systemic azoles dramatically increase the serum concentrations of co-administered drugs that are substrates of these enzymes.
For transplant and oncology patients, this is a critical safety issue. Azoles increase the levels of calcineurin inhibitors (cyclosporine, tacrolimus) and mTOR inhibitors (sirolimus), leading to acute nephrotoxicity (reflected in 3,131 acute kidney injury reports) and neurotoxicity. They also interact with oral anticoagulants, statins, and chemotherapy agents (such as vincristine, where azole-induced CYP3A4 inhibition can cause severe, irreversible peripheral neuropathy). The prominence of the drug-interaction signal in FAERS highlights the real-world challenge of managing these complex regimens.
How do the QT-prolonging azoles compare with isavuconazole (QT-shortening)?
Another major safety concern with the azole class is QT prolongation, which can lead to life-threatening ventricular arrhythmias, including Torsades de Pointes (TdP). In a published disproportionality analysis of the FAERS database (Frontiers in Pharmacology 2024), 11.46 percent of triazole-related adverse events were cardiac in nature.
The risk of QT prolongation is not uniform across the class:
- Fluconazole, Voriconazole, and Posaconazole: These agents block the hERG potassium channel, leading to prolongation of the cardiac action potential. This effect is dose-dependent and exacerbated by hepatic impairment or drug interactions that increase azole concentrations.
- Isavuconazole (Isavuconazonium sulfate): In contrast to the other class members, isavuconazole does not prolong the QT interval; instead, it is clinically associated with QT shortening. This makes isavuconazole a preferred option for patients with pre-existing long QT syndrome or those who must take concomitant QT-prolonging therapies.
The low report count for isavuconazonium sulfate (3,065 reports) in FAERS reflects both its later market entry and its favorable cardiac safety profile. P&T committees frequently utilize isavuconazole's unique QT-shortening property to justify its higher acquisition cost in patients with significant cardiac risk factors.
Why is the indication profile dominated by AML, myeloma, and prophylaxis?
Looking at the indications for azole antifungal therapy in the FAERS database reveals a strong concentration of high-acuity medical conditions:
| Indication | Reports | Share of Class |
|---|---|---|
| Product used for unknown indication | 48,554 | 32.1% |
| Prophylaxis | 11,578 | 7.7% |
| Fungal infection | 8,276 | 5.5% |
| Antifungal prophylaxis | 7,980 | 5.3% |
| Acute myeloid leukaemia | 7,755 | 5.1% |
| Hypertension | 5,714 | 3.8% |
| Plasma cell myeloma | 5,273 | 3.5% |
| Pain | 5,138 | 3.4% |
| Bronchopulmonary aspergillosis | 4,211 | 2.8% |
| Infection prophylaxis | 4,134 | 2.7% |
| Aspergillus infection | 4,020 | 2.7% |
Prophylaxis and antifungal prophylaxis combined account for 13.0 percent of the cohort, while acute myeloid leukemia (5.1 percent) and plasma cell myeloma (3.5 percent) represent the primary oncological indications.
This distribution is clinical-use consistent. Patients with AML undergoing induction chemotherapy, or those with multiple myeloma receiving proteasome inhibitors and high-dose dexamethasone, have severe, prolonged neutropenia. This status places them at high risk for invasive fungal infections. In these settings, posaconazole and voriconazole are prophylactic therapies. The high incidence of serious adverse events in these reports (including death, febrile neutropenia, and pneumonia) is primarily a function of the underlying malignancy and the intensive chemotherapy regimens rather than the safety profile of the antifungal drugs.
How are topical/OTC azoles (clotrimazole, miconazole, ketoconazole) handled in a substance-level cut?
A major challenge in pharmacovigilance is that spontaneous reporting databases compile adverse events at the substance level, meaning that topical (vaginal creams, shampoos) and systemic (oral/IV) formulations of the same drug are grouped together.
For example:
- Clotrimazole (10,748 reports) and Miconazole nitrate (5,021 reports) are primarily used as topical or vaginal preparations for vulvovaginal candidiasis.
- Ketoconazole (13,404 reports) is widely used topically for seborrheic dermatitis, but it is also used systemically for Cushing's syndrome.
Because FAERS does not systematically separate reports by route of administration in its public extract, these topical/OTC reports are included in the class-wide totals. This "topical contamination" artificially inflates the size of the class footprint while diluting the serious adverse-event rates associated with systemic azoles. For example, a vaginal clotrimazole report for localized irritation is counted alongside a systemic voriconazole report for hepatotoxicity. P&T committees and clinical researchers must keep this limitation in mind when interpreting class-wide safety signals.
Clinical Management: Therapeutic Drug Monitoring (TDM) Protocols
To mitigate the safety risks identified in FAERS — specifically hepatotoxicity and subtherapeutic drug levels leading to treatment failure — clinical protocols for systemic triazoles must emphasize Therapeutic Drug Monitoring (TDM).
- Voriconazole TDM: Voriconazole exhibits non-linear (saturated) pharmacokinetics in adults, and its metabolism is influenced by CYP2C19 polymorphisms (rapid vs. poor metabolizers). The target trough concentration range is 1.0 to 5.0 mcg/mL. Troughs < 1.0 mcg/mL are associated with treatment failure (drug ineffective), while troughs > 5.0 mcg/mL significantly increase the risk of neurotoxicity (visual hallucinations, confusion) and hepatotoxicity.
- Posaconazole TDM: Posaconazole suspension has variable absorption and must be administered with a high-fat meal. The newer delayed-release tablet and IV formulations provide more predictable exposure. For prophylaxis, the target trough is > 0.7 mcg/mL, whereas for active treatment of invasive infection, the target is > 1.0 mcg/mL.
Implementing standardized TDM protocols in oncology and transplant units reduces the incidence of both subtherapeutic failures and toxic exposures, directly addressing the safety signals highlighted in real-world data.
FAQs
Does the 17.1% death rate mean azole antifungals are the most dangerous class in FAERS?
No. The 17.1 percent mortality rate reflects the high-risk patient population taking these medications. Patients with acute myeloid leukemia, bone marrow transplants, and invasive aspergillosis have a high baseline mortality rate due to their underlying diseases. Spontaneous reports capture deaths that occur while a patient is on the drug, which in this case represents the severity of the clinical scenario rather than drug toxicity.
Why is isavuconazole's report count so much lower than fluconazole's?
Isavuconazonium sulfate (3,065 reports) is a newer, specialty agent approved in 2015 for niche indications (invasive aspergillosis and mucormycosis) and is primarily used in hospital settings. In contrast, fluconazole (59,511 reports) is an older, generic, widely prescribed drug used for common, non-life-threatening infections like vaginal candidiasis.
Are PPIs (omeprazole, pantoprazole) included in the azole cut, and why or why not?
No. While proton pump inhibitors (PPIs) contain the "azole" string in their generic names, they are benzimidazole compounds with a completely different mechanism of action and safety profile. They are excluded from this antifungal cut to prevent data contamination and are analyzed separately in proton pump inhibitor adverse events by the numbers.
How should a transplant formulary interpret the drug-interaction signal?
The drug-interaction signal (5.3 percent of reports) highlights the need for active drug monitoring (TDM). When starting a systemic azole in a patient on cyclosporine, tacrolimus, or sirolimus, dose reductions of the immunosuppressant (often by 30 to 75 percent) are mandatory, followed by close serum level monitoring to prevent toxicity.
What are the liver safety profiles of different systemic azoles?
All systemic azoles can cause hepatotoxicity, ranging from transient elevation of transaminases to acute liver failure. Ketoconazole carries the highest risk and has a boxed warning for hepatotoxicity. Among the triazoles, voriconazole and itraconazole are associated with higher rates of liver enzyme elevations compared to fluconazole and isavuconazole.
Can oral azoles be used in pregnant patients?
Generally, systemic azoles (especially fluconazole and voriconazole) should be avoided during the first trimester of pregnancy due to risks of congenital malformations (including cardiac and craniofacial defects). If a fungal infection is life-threatening, the clinical benefits must be weighed against these fetal risks. Topical azoles are preferred for localized infections in pregnant patients.
Sources
- U.S. Food and Drug Administration (FDA). FDA Adverse Event Reporting System (FAERS) public data extract (export dated June 8, 2026). https://open.fda.gov/data/faers/
- Wang, Y., et al. (2024). Evaluating cardiac disorders associated with triazole antifungal agents based on the FDA Adverse Event Reporting System. Frontiers in Pharmacology, 15, Article 1255918. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1255918/full
- Zonouzi, S., et al. (2023). Hepatotoxicity Induced by Azole Antifungal Agents: A Review Study. Iranian Journal of Pharmaceutical Research, 22(1), e10728840. https://pmc.ncbi.nlm.nih.gov/articles/PMC10728840
- Mastroianni, A., et al. (2024). QTc Interval Prolongation as an Adverse Event of Azole Antifungal Drugs: Case Report and Literature Review. Microorganisms, 12(8), 1619. https://www.mdpi.com/2076-2607/12/8/1619
- Kyriakidis, I., et al. (2019). Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents. Drugs, 79(11), 1177-1194. https://link.springer.com/article/10.1007/s40265-019-01127-8
