Update on the recent study findings on the risk of non-melanoma skin cancer with prolonged use of hydrochlorothiazide

HSA would like to update healthcare professionals on two recent pharmacoepidemiological studies using data from Danish registries which suggested a cumulative dose-dependent association between the prolonged use of hydrochlorothiazide-containing medicines and non-melanoma skin cancer (NMSC).

Hydrochlorothiazide is a diuretic that is commonly used alone or in combination with other antihypertensives for the treatment of hypertension. High cumulative usage of hydrochlorothiazide (i.e. ≥50,000mg, corresponding to 12.5mg daily for 11 years) was found to be associated with an increased risk of basal cell carcinoma (BCC) (adjusted odds ratio [OR]=1.29; 95% CI=1.23-1.35) and squamous cell carcinoma (SCC) (OR=3.98; 95% CI=3.68-4.31).

HSA is currently assessing the available data on this potential risk, including the two studies, and will provide an update on our regulatory recommendations upon the completion of our review.   

Findings from Danish pharmacoepidemiological studies

Two recent pharmacoepidemiological studies using data from Danish registries had found a cumulative dose-dependent association between hydrochlorothiazide use and NMSC.

One study included 71,533 patients with BCC and 8,629 patients with SCC, who were matched with population controls in a 1:20 ratio by age and sex.1 Patients with organ transplantation, HIV diagnosis or use of immunosuppressive agents were excluded, as these might predispose to skin cancer. High cumulative usage of hydrochlorothiazide (i.e. ≥50,000mg, corresponding to 12.5mg daily for about 11 years) was found to be associated with an increased risk of BCC (adjusted odds ratio [OR]=1.29; 95% CI=1.23-1.35) and SCC (OR=3.98; 95% CI=3.68-4.31). The respective ORs were based on high use of hydrochlorothiazide in 2.7% of patients and 2.1% of controls in the BCC group, and 10% of patients and 2.8% of controls in the SCC group. Notably, a clear dose-response pattern was observed in this study for both BCC and SCC, with a more than 7-fold increased risk of SCC for cumulative use of ≥200,000mg hydrochlorothiazide (BCC: OR=1.54; 95% CI=1.38-1.71; SCC: OR=7.38; 95% CI=6.32-8.60).

In another Danish study, which included 633 cases with SCC of the lip, matched with 63,067 population controls,2 a cumulative dose‐response relationship between the use of hydrochlorothiazide and SCC of the lip was also demonstrated. The adjusted OR with ever-use of hydrochlorothiazide was 2.1 (95% CI=1.7-2.6), which increased to 3.9 (95% CI=3.0‐4.9) and 7.7 (95%CI=5.7‐10.5) with high cumulative hydrochlorothiazide use of ≥25,000mg and ≥100,000mg, respectively.

International regulatory actions

Following the publication of the two Danish case control studies, the European Medicines Agency (EMA)3, Health Canada4 and New Zealand Medsafe5 conducted safety reviews on the risk of NMSC associated with the use of hydrochlorothiazide. EMA had considered that there was a biologically plausible mechanistic model supporting the increased risk of NMSC following higher cumulative doses of hydrochlorothiazide, while Health Canada concluded NMSC is a potential risk of prolonged hydrochlorothiazide treatment. However, uncertainty remains due to limitations noted in the reviewed studies. All three agencies recommended that the package inserts (PIs) of hydrochlorothiazide-containing products be strengthened on the risk of NMSC. Patients taking hydrochlorothiazide are encouraged to practise preventive measures such as limiting the exposure to sunlight and ultraviolet (UV) rays to minimise risk of skin cancer.  

Local situation and HSA’s advisory

From 2011 to 2015, the incidence rates of skin cancer in Singaporean men and women were 19.3 and 14.4 per 100,000 person-years, respectively.6 The most common type of skin cancer is NMSC, which consists mainly of SCC and BCC.7 The known risk factors for NMSC include, but are not limited to UV exposure, immunosuppression, photosensitising medications, and fair or light skin complexion.8

The possible mechanism of NMSC attributed by hydrochlorothiazide was postulated to be due to the photosensitising actions of hydrochlorothiazide, which might influence cancer risk at sun-exposed sites, as well as induce a chronic inflammatory reaction.9,10 

To date, HSA has not received any local reports of NMSC suspected to be associated with the use of hydrochlorothiazide. Three product registrants of hydrochlorothiazide-containing products have sent out Dear Healthcare Professional Letters to inform healthcare professionals about this safety issue as part of their global safety action plans. These companies have also begun updating the Singapore PIs for hydrochlorothiazide-containing products to include information on the observed increased risk of NMSC reported in the pharmacoepidemiological studies, as well as preventive measures to consider for patients taking hydrochlorothiazide.

As the incidence rates of NMSC vary across different countries and the baseline risks are dependent on factors such as skin phenotypes, HSA is reviewing the evidence from the study findings and other relevant data to assess the safety risks in the local context to determine if other regulatory actions are needed.

While HSA’s safety review is ongoing, healthcare professionals should consider the findings from the two Danish pharmacoepidemiological studies when prescribing hydrochlorothiazide to their patients. HSA will provide an update on the outcome of our review when it is completed. Healthcare professionals are encouraged to report any suspected cases of NMSC related to hydrochlorothiazide to HSA.

References

  1. J Am Acad Dermatol 2018; 78:673‐81
  2. J Intern Med 2017; 282: 322–31
  3. https://www.ema.europa.eu/documents/minutes/minutes-prac-meeting-3-6-september-2018_en.pdf
  4. https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00215
  5. https://medsafe.govt.nz/profs/adverse/Minutes176.htm#3.2.1
  6. https://www.nrdo.gov.sg/docs/librariesprovider3/Publications-Cancer/cancer-registry-annual-report-2015_web.pdf
  7. J Am Acad Dermatol 2009; 61:426-32
  8. Semin Oncol Nurs 2013; 29:160-9
  9. Photochem Photobiol 2013; 89: 649–54
  10. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 2016; 108: 285-318
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