The Position of the Croatian Society of Hypertension on the Observed Increase in Risk of Non-melanoma Skin Cancer Associated with Hydrochlorothiazide Treatment

    Authors

    Abstract

    The Governing Board of the Croatian Society of Hypertension held an e-meeting on December 12, 2018, where the observed increase in risk of non-melanoma skin cancer associated with hydrochlorothiazide treatment was discussed, and the following statement was prepared. On October 1, 2018, the European Medicines Agency (EMA) published a warning on the increased risk of non-melanoma skin cancer associated with higher cumulative hydrochlorothiazide doses (1). Their recommendation was to inform the patients of the risk and that patients receiving this treatment should undergo regular skin examinations. Other recommended preventive measures include avoiding exposure to sunlight, ultraviolet (UV) radiation, and the use of appropriate protection. Continued hydrochlorothiazide treatment should be reconsidered in patients who were previously treated for non-melanoma skin cancer. The Agency for Medical Products and Medical Devices of Croatia (HALMED; Hrvatska agencija za lijekove i medicinske proizvode) has published a statement on November 22, 2018 in which they warn of the slightly increased risk of non-melanoma skin cancer due to exposure to high cumulative doses of hydrochlorothiazide, with the conclusion that the benefits of hydrochlorothiazide application outweigh the potential risks (2). HALMED’s recommendation is for patients to continue with the application of the prescribed treatment and that self-induced treatment termination can cause serious harm to patients. The advice is for patients to regularly check their skin for possible manifestations of any new lesions or changes in existing ones. It is also recommended that patients limit exposure to sunlight and UV radiation. HALMED provided a list of medications containing hydrochlorothiazide that are on the market in the Republic of Croatia (2), as shown in **Table 1**. ### TABLE 1: List of medications containing hydrochlorothiazide that are on the market in the Republic of Croatia ( 2 ). | Amicor H | Enap-H | Laaven-HL | Monopril plus | Prinzide | Valnorm H | | --- | --- | --- | --- | --- | --- | | Ampril HD | Enap-HL | Lizinopril H Farmal | Nebilet plus | Ramicomp Genericon | Valsacombi | | Ampril HL | Exforge HCT | Lodoz | Olmesartan/hidroklorotiazid Genericon | Ramipril H Farmal | Vitozid | | Blocar Plus | Fortzaar | Lorista H | Optimon Plus | Ramzid | Zofecard Plus | | Cilazil Plus | Hyzaar | Lorista HD | Osan Plus | Skopryl plus | | | CoAprovel | Iruzid | Losartic Plus | Piramil H | Tolucombi | | | Co-Cazaprol | Kandapres Plus | Lotan H | Piramil HL | Tritazide | | | Co-Diovan | Laaven-HD | MicardisPlus | Prilen Plus | Val plus | | This warning is a result of the publication of the results obtained from data analysis performed on a Danish registry (3, 4). However, there had been earlier papers reporting the possible association between thiazide diuretics and risk of skin and lip carcinoma (5-7). What caused special attention in the Danish results was confirmation of the importance of cumulative doses, i.e. that the risk is greater for higher cumulative doses. A cause for concern and caution is also the fact that with a dose of 12.5 mg daily, which is the most commonly applied dose in our region, the cumulative dose after five years of treatment is equal to 22.812 mg, with an OR for risk of lip carcinoma of 3.9 (3.0-4.9) and the risk of skin cancer after ten years at OR 1.29 (1.23-1.35) for basal-cell carcinoma and OR 3.98 (3.68-4.31) for squamous cell carcinoma (3, 4). Similar data, but with a lower level of significance, were also obtained in the Kaiser Permanente Northern California US cohort (8). Although these studies have certain strengths, they have limitations as well. The fact that increased risk of these carcinomas with cumulative doses of hydrochlorothiazide has been observed cannot and must not be ignored. However, we must also be aware of the fact that the benefits of the application of thiazide diuretics is several times greater than the risk of carcinoma, which is especially evident in elderly persons, patients with heart failure, and those with a shorter life expectancy (9). It is also important to note that these carcinomas can be diagnosed early and in a timely manner if the patients are properly informed on how to monitor changes on the skin and lips.

    DOI

    https://doi.org/10.15836/ccar2019.21

    Literature

    1. European Medicines Agency. PRAC recommendations on signals Adopted at the 3-6 September 2018 PRAC meeting. 1.5. Hydrochlorothiazide – Skin cancer. Avaialable from: (December 12, 2018). https://www.ema.europa.eu/documents/prac-recommendation/prac-recommendations-signals-adopted-3-6-september-2018-prac-meeting_en-0.pdf
    2. Agencija za lijekove i medicinske proizvode (HALMED). Sigurnost primjene lijekova koji sadrže hidroklorotiazid. Available from: (December 12, 2018). http://www.halmed.hr/Novosti-i-edukacije/Novosti/2018/Sigurnost-primjene-lijekova-koji-sadrze-hidroklorotiazid-/2057/
    3. Pottegård A, Hallas J, Olesen M, Svendsen MT, Habel LA, Friedman GD, et al. Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med. 2017 Oct;282(4):322–31. https://doi.org/10.1111/joim.12629
    4. Pedersen SA, Gaist D, Schmidt SAJ, Hölmich LR, Friis S, Pottegård A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol. 2018 Apr;78(4):673–681.e9. https://doi.org/10.1016/j.jaad.2017.11.042
    5. de Vries E, Trakatelli M, Kalabalikis D, Ferrandiz L, Ruiz-de-Casas A, Moreno-Ramirez D, et al. EPIDERM Group. Known and potential new risk factors for skin cancer in European populations: a multicentre case-control study. Br J Dermatol. 2012 Aug;167 Suppl 2:1–13. https://doi.org/10.1111/j.1365-2133.2012.11081.x
    6. Friedman GD, Asgari MM, Warton EM, Chan J, Habel LA. Antihypertensive drugs and lip cancer in non-Hispanic whites. Arch Intern Med. 2012 Sep 10;172(16):1246–51. https://doi.org/10.1001/archinternmed.2012.2754
    7. Nardone B, Majewski S, Kim AS, Kiguradze T, Martinez-Escala EM, Friedland R, et al. Melanoma and Non-Melanoma Skin Cancer Associated with Angiotensin-Converting-Enzyme Inhibitors, Angiotensin-Receptor Blockers and Thiazides: A Matched Cohort Study. Drug Saf. 2017 Mar;40(3):249–55. https://doi.org/10.1007/s40264-016-0487-9
    8. Su KA, Habel LA, Achacoso NS, Friedman GD, Asgari MM. Photosensitizing antihypertensive drug use and risk of cutaneous squamous cell carcinoma. Br J Dermatol. 2018 Nov;179(5):1088–94. https://doi.org/10.1111/bjd.16713
    9. Messerli FH. Diuretic therapy and renal cell carcinoma--another controversy? Eur Heart J. 1999 Oct;20(20):1441–2. https://doi.org/10.1053/euhj.1999.1534
    Cardiologia Croatica
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    The Position of the Croatian Society of Hypertension on the Observed Increase in Risk of Non-melanoma Skin Cancer Associated with Hydrochlorothiazide Treatment

    Editorial
    Issue1-2
    Published
    Pages21-23
    PDF via DOIhttps://doi.org/10.15836/ccar2019.21

    Authors

    Bojan Jelaković*ORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Ines DrenjančevićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Mario LaganovićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Ivan PećinORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Ana JelakovićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Maja BaretićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Živka DikaORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Mario IvanušaORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Vesna Herceg-ČavrakORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Josipa JosipovićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Verica KraljORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Ninoslav LekoORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Robert LikićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Martina Lovrić BenčićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Lidija OrlićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Draško PavlovićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Darko PočanićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Ingrid PrkačinORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Ranko StevanovićUpravni odbor, Hrvatsko društvo za hipertenziju
    Hrvoje TiljakORCIDUpravni odbor, Hrvatsko društvo za hipertenziju
    Tajana Željković VrkićORCIDUpravni odbor, Hrvatsko društvo za hipertenziju

    *Correspondence email: predsjednik@hdh.hr

    Abstract

    The Governing Board of the Croatian Society of Hypertension held an e-meeting on December 12, 2018, where the observed increase in risk of non-melanoma skin cancer associated with hydrochlorothiazide treatment was discussed, and the following statement was prepared. On October 1, 2018, the European Medicines Agency (EMA) published a warning on the increased risk of non-melanoma skin cancer associated with higher cumulative hydrochlorothiazide doses (1). Their recommendation was to inform the patients of the risk and that patients receiving this treatment should undergo regular skin examinations. Other recommended preventive measures include avoiding exposure to sunlight, ultraviolet (UV) radiation, and the use of appropriate protection. Continued hydrochlorothiazide treatment should be reconsidered in patients who were previously treated for non-melanoma skin cancer. The Agency for Medical Products and Medical Devices of Croatia (HALMED; Hrvatska agencija za lijekove i medicinske proizvode) has published a statement on November 22, 2018 in which they warn of the slightly increased risk of non-melanoma skin cancer due to exposure to high cumulative doses of hydrochlorothiazide, with the conclusion that the benefits of hydrochlorothiazide application outweigh the potential risks (2). HALMED’s recommendation is for patients to continue with the application of the prescribed treatment and that self-induced treatment termination can cause serious harm to patients. The advice is for patients to regularly check their skin for possible manifestations of any new lesions or changes in existing ones. It is also recommended that patients limit exposure to sunlight and UV radiation. HALMED provided a list of medications containing hydrochlorothiazide that are on the market in the Republic of Croatia (2), as shown in **Table 1**. ### TABLE 1: List of medications containing hydrochlorothiazide that are on the market in the Republic of Croatia ( 2 ). | Amicor H | Enap-H | Laaven-HL | Monopril plus | Prinzide | Valnorm H | | --- | --- | --- | --- | --- | --- | | Ampril HD | Enap-HL | Lizinopril H Farmal | Nebilet plus | Ramicomp Genericon | Valsacombi | | Ampril HL | Exforge HCT | Lodoz | Olmesartan/hidroklorotiazid Genericon | Ramipril H Farmal | Vitozid | | Blocar Plus | Fortzaar | Lorista H | Optimon Plus | Ramzid | Zofecard Plus | | Cilazil Plus | Hyzaar | Lorista HD | Osan Plus | Skopryl plus | | | CoAprovel | Iruzid | Losartic Plus | Piramil H | Tolucombi | | | Co-Cazaprol | Kandapres Plus | Lotan H | Piramil HL | Tritazide | | | Co-Diovan | Laaven-HD | MicardisPlus | Prilen Plus | Val plus | | This warning is a result of the publication of the results obtained from data analysis performed on a Danish registry (3, 4). However, there had been earlier papers reporting the possible association between thiazide diuretics and risk of skin and lip carcinoma (5-7). What caused special attention in the Danish results was confirmation of the importance of cumulative doses, i.e. that the risk is greater for higher cumulative doses. A cause for concern and caution is also the fact that with a dose of 12.5 mg daily, which is the most commonly applied dose in our region, the cumulative dose after five years of treatment is equal to 22.812 mg, with an OR for risk of lip carcinoma of 3.9 (3.0-4.9) and the risk of skin cancer after ten years at OR 1.29 (1.23-1.35) for basal-cell carcinoma and OR 3.98 (3.68-4.31) for squamous cell carcinoma (3, 4). Similar data, but with a lower level of significance, were also obtained in the Kaiser Permanente Northern California US cohort (8). Although these studies have certain strengths, they have limitations as well. The fact that increased risk of these carcinomas with cumulative doses of hydrochlorothiazide has been observed cannot and must not be ignored. However, we must also be aware of the fact that the benefits of the application of thiazide diuretics is several times greater than the risk of carcinoma, which is especially evident in elderly persons, patients with heart failure, and those with a shorter life expectancy (9). It is also important to note that these carcinomas can be diagnosed early and in a timely manner if the patients are properly informed on how to monitor changes on the skin and lips.

    Literature

    1. 1.
      European Medicines Agency. PRAC recommendations on signals Adopted at the 3-6 September 2018 PRAC meeting. 1.5. Hydrochlorothiazide – Skin cancer. Avaialable from: (December 12, 2018).Link
    2. 2.
      Agencija za lijekove i medicinske proizvode (HALMED). Sigurnost primjene lijekova koji sadrže hidroklorotiazid. Available from: (December 12, 2018).Link
    3. 3.
      Pottegård A, Hallas J, Olesen M, Svendsen MT, Habel LA, Friedman GD, et al. Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med. 2017 Oct;282(4):322–31.DOI
    4. 4.
      Pedersen SA, Gaist D, Schmidt SAJ, Hölmich LR, Friis S, Pottegård A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol. 2018 Apr;78(4):673–681.e9.DOI
    5. 5.
      de Vries E, Trakatelli M, Kalabalikis D, Ferrandiz L, Ruiz-de-Casas A, Moreno-Ramirez D, et al. EPIDERM Group. Known and potential new risk factors for skin cancer in European populations: a multicentre case-control study. Br J Dermatol. 2012 Aug;167 Suppl 2:1–13.DOI
    6. 6.
      Friedman GD, Asgari MM, Warton EM, Chan J, Habel LA. Antihypertensive drugs and lip cancer in non-Hispanic whites. Arch Intern Med. 2012 Sep 10;172(16):1246–51.DOI
    7. 7.
      Nardone B, Majewski S, Kim AS, Kiguradze T, Martinez-Escala EM, Friedland R, et al. Melanoma and Non-Melanoma Skin Cancer Associated with Angiotensin-Converting-Enzyme Inhibitors, Angiotensin-Receptor Blockers and Thiazides: A Matched Cohort Study. Drug Saf. 2017 Mar;40(3):249–55.DOI
    8. 8.
      Su KA, Habel LA, Achacoso NS, Friedman GD, Asgari MM. Photosensitizing antihypertensive drug use and risk of cutaneous squamous cell carcinoma. Br J Dermatol. 2018 Nov;179(5):1088–94.DOI
    9. 9.
      Messerli FH. Diuretic therapy and renal cell carcinoma--another controversy? Eur Heart J. 1999 Oct;20(20):1441–2.DOI