Drug products: Amiloferm®, Amiloferm® mite, Atacand Plus, Atacand® Plus, Blopresid Comp, Blopress Comp, Candemox Comp, Candesarstad Comp, Candesartan/Hydrochlorothiazide 2care4, Candesartan/Hydrochlorothiazide Actavis, Candesartan/Hydrochlorothiazide Krka, Candesartan/Hydrochlorothiazide Navamedic, Candesartan/Hydrochlorothiazide Orion, Candesartan/Hydrochlorothiazide STADA, Candesartan/Hydrochlorothiazide Teva, Candexetil comp, Corixil Comp, Cozaar Comp, Cozaar® Comp, Cozaar® Comp Forte, Diovan Comp, Diovan® Comp, Enalapril comp ratiopharm, Enalapril Comp Sandoz, Enalapril Comp STADA®, Enalapril/Hydrochlorothiazide 2care4, Enalapril/Hydrochlorothiazide Mylan, Enalapril/Hydrochlorothiazide Orion, Enalapril/Hydrochlorothiazide Teva, Esidrex®, Fortzaar Comp Forte, Forzaar Comp Forte, Hydrochlorothiazide Bluefish, Hydrochlorothiazide Orifarm, Hydrochlorothiazide Orion, Hydroklortiazid Ebb, Hydroklortiazid Evolan, Klomentan Comp, Linatil comp, Linatil comp mite, Lisinopril/Hydrochlorthiazid Sandoz, Lisinopril/Hydroklortiazid Actavis, Lisinopril/Hydroklortiazid Copyfarm, Lisinopril/Hydroklortiazid STADA, Losamyl Comp, Losarstad Comp, Losartan/Hydrochlorothiazide Aurobindo, Losartan/Hydrochlorothiazide Bluefish, Losartan/Hydrochlorothiazide Krka, Losartan/Hydrochlorothiazide Medical Valley, Losartan/Hydrochlorothiazide Sandoz, Losartan/Hydrochlorothiazide Teva, Losartan/Hydroklortiazid Actavis, Losartan/hydroklortiazid Jubilant, Losartan/Hydroklortiazid Orifarm, Losatrix comp, Losatrix Comp, Losazid Comp, Losazid Comp Forte, Marozid, Moduretic, Moduretic®, Moduretic® mite, Normorix, Normorix mite, Ramipril/Hydrochlorothiazide Krka, Ramipril/Hydroklortiazid 2care4, Ramipril/Hydroklortiazid Actavis, Ramipril/Hydroklortiazid Alternova, Ramipril/Hydroklortiazid Ebb, Ramipril/Hydroklortiazid HEXAL, Ramipril/Hydroklortiazid Orifarm, Ratacand Plus, Renitec® comp., Sparkal®, Sparkal® mite, Synerpril®, Tanlozid, Tareg Comp, Triatec® comp, Triatec® comp mite, Valsartan/Hydrochlorothiazide 2care4, Valsartan/Hydrochlorothiazide Krka, Valsartan/Hydrochlorothiazide Sandoz, Valsartan/Hydrochlorothiazide Teva, Valsartan/Hydroklortiazid Actavis, Valsartan/Hydroklortiazid Ebb, Valsartan/Hydroklortiazid Jubilant, Valsartore Comp, Valtsu comp, Zestoretic
ATC code: C03AA03, C03EA01, C09BA02, C09BA03, C09BA05, C09DA01, C09DA03, C09DA06
Studies have shown contradictory results on differences in the blood pressure lowering effect of hydrochlorothiazide in men and women.
Spontaneous reports of serious adverse drug reactions of hydrochlorothiazide, such as acute pulmonary edema and acute allergic interstitial pneumonia, have been more common in women than in men. Squamous cell carcinoma (not lip) has been shown to be higher in women while other non-melanoma skin cancer no sex-differences have been reported.
No studies with a clinically relevant sex analysis regarding the pharmacokinetics or dosing of hydrochlorothiazide have been found.
Studies report conflicting results on sex differences in response to hydrochlorothiazide (HCTZ ). Results from the randomized, double-blind HANE study (113 men, 102 women) showed similar antihypertensive response rates to HCTZ (12.5-50 mg daily over 48 weeks) between men and women . However, a prospective clinical trial (1209 men, 2326 women) found that women had a better diastolic BP response to HCTZ (12.5-25 mg daily for 8 weeks) than men. Women were 57% more likely to reach the control goal of diastolic BP than men . Also a small randomized clinical trial (29 men, 23 women) showed that women had higher systolic/diastolic ambulatory BP response to HCTZ than men after 25 mg daily for 4 weeks .
Diuretic response to 50 mg oral HCTZ was measured in healthy volunteers (6 men, 6 women) in a randomized, cross-over study. No clinical relevant sex differences in diuretic response, urine flow rate, potassium excretion rate and natriuretic response were found .
Large pharmacoepidemiological studies have shown an increased risk of non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma) after exposure of increased cumulative doses of HCTZ [5-7]. Men and women had similar risk of lip cancer  and basal cell carcinoma , while the risk of squamous cell carcinoma (not lip) was higher in women (OR 4.46; 95%CI 4.04-4.94) than in men (OR 3.26; 95%CI 2.85-3.72) [5, 6].
HCTZ-induced acute pulmonary edema has been described as a rare adverse event. In a review of reported cases, 16 out of 17 patients were women .
Cases of acute allergic interstitial pneumonitis induced by HCTZ have been described in the literature. In a series of case reports, female sex was reported as a risk factor, since 27 (90%) of the 30 described patients were women, mostly postmenopausal .
Hyponatremia is reported to be more common in women treated with HCTZ. A medical record review of patients with hyponatremia treated with diuretics (31 men, 149 women) revealed that women had three times higher risk of hyponatremia than men in all age groups (OR 3.10, 95%CI 2.07-4.67). Almost all received HCTZ (75%). Duration of diuretic treatment was only reported in 57 patients; 44% of the patients had developed hyponatremia within 1 month of treatment and 45% after 6 months . In another review of medical records, female sex was a risk factor for hyponatremia among patients treated with HCTZ or indapamide (391 men and 608 women on HCTZ) .
Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).
Studies have found interacting effects between patient’s sex and ACE genotype on blood pressure response to HCTZ in blacks, whites  and Han Chinese patients  with hypertension. The genotypes associated with the greatest decline in blood pressure were DD homozygotes in men and II homozygotes in women [12, 13].
A Canadian cohort study evaluating age and sex-related use of thiazide diuretics and beta-blockers showed that women were 8% more likely than men to be dispensed a low-dose thiazide diuretic (OR 1.08, 95% CI 1.05-1.11) .
Date of litterature search: 2019-03-08
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson