IARC Monographs evaluation of the carcinogenicity of hydrochlorothiazide, voriconazole, and tacrolimus

The International Agency for Research on Cancer (IARC), the cancer agency of the World Health Organization (WHO), has evaluated the carcinogenicity of hydrochlorothiazide, voriconazole, and tacrolimus. The outcome of the assessment has been published in a summary article in The Lancet Oncology and will be described in detail in Volume 137 of the IARC Monographs, to be published in 2025.

Hydrochlorothiazide and other phototoxic drugs were accorded high priority by the Advisory Group to Recommend Priorities for the IARC Monographs during 2020–2024. Hydrochlorothiazide was previously evaluated by the IARC Monographs in Volumes 50 and 108. Voriconazole and tacrolimus were evaluated for the first time.

Hydrochlorothiazide is the most common prescription-only oral thiazide diuretic drug used worldwide to treat essential hypertension and peripheral oedema. Although partly replaced by other antihypertensives, hydrochlorothiazide remains a commonly prescribed drug. It is frequently used in a single-pill combination that also contains angiotensin receptor blockers. Interaction of the hydrochlorothiazide molecule with ultraviolet radiation leads to phototoxicity.

Voriconazole is a broad-spectrum triazole drug used as curative treatment or prophylaxis for invasive aspergillosis and other serious fungal infections, which are especially common in transplant recipients. It is approved in most countries worldwide for use in adults and children (age > 2 years). The major metabolite, voriconazole N-oxide, is phototoxic.

Tacrolimus is a calcineurin inhibitor used in oral and intravenous formulations as an immunosuppressive medication to reduce the risk of rejection of solid organ transplants in adults and children, and to prevent graft-versus-host disease. Topical tacrolimus is a second-line therapy for the treatment of atopic dermatitis and vitiligo. Information regarding the phototoxicity of tacrolimus is scarce.

Hydrochlorothiazide, voriconazole, and tacrolimus are all listed in the World Health Organization Model List of Essential Medicines. The main exposures to hydrochlorothiazide, voriconazole, and tacrolimus are from medications.

The Working Group evaluated hydrochlorothiazide, voriconazole, and tacrolimus as carcinogenic to humans (Group 1) on the basis of sufficient evidence for cancer in humans for each agent. For tacrolimus, a Group 1 evaluation was also reached on the basis of sufficient evidence for cancer in experimental animals and strong mechanistic evidence in exposed humans.

There was sufficient evidence that hydrochlorothiazide causes squamous cell carcinoma of the skin and cancer of the lip in humans. The evidence was limited for a causal association between hydrochlorothiazide and basal cell carcinoma of the skin, melanoma of the skin, Merkel cell carcinoma, and malignant adnexal skin tumours. There was also sufficient evidence for cancer in experimental animals and limited mechanistic evidence.

There was sufficient evidence that voriconazole causes squamous cell carcinoma of the skin in humans. There was also strong mechanistic evidence in combination with ultraviolet radiation in exposed humans (for alteration of cell proliferation, cell death, or nutrient supply) and human primary cells (for oxidative stress).

There was sufficient evidence that tacrolimus causes non-Hodgkin lymphoma and post-transplant lymphoproliferative disorder. The evidence was limited for a causal association between tacrolimus and leukaemia and squamous cell carcinoma of the skin in humans. There was also sufficient evidence for cancer in experimental animals and strong mechanistic evidence for immunosuppression across all test systems, including exposed humans, and for genotoxicity and oxidative stress in experimental systems.

The full scientific assessment will be published as Volume 137 of the IARC Monographs.

Cogliano V, Corsini E, Fournier A, Nelson HH, Sergi CM, Antunes AMM, et al.
Carcinogenicity of hydrochlorothiazide, voriconazole, and tacrolimus
Lancet Oncol. Published online 29 November 2024;
https://doi.org/10.1016/S1470-2045(24)00685-5

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