Health Canada has reviewed the potential risks of choroidal effusion (CE), acute myopia (AM), and acute angle-closure glaucoma (AACG) with the use of certain diuretics, including hydrochlorothiazide, chlorthalidone, indapamide, and acetazolamide. Health Canada has concluded that there is a link between the use of these medications and the risks of CE with AM or with AACG or with both AM and AACG; Health Canada's review also concluded that there might be a link between metolazone and the risk of these ophthalmic disorders. Health Canada is working with manufacturers to update the Canadian product safety information for these products to add a warning about these risks.
Further information may be found at https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00261.
Calcium nephrolithiasis, prevention (off-label use):
Note: Use for patients with high urine calcium that is not due to hypercalcemia (AUA [Pearle 2014]; Curhan 2021).
Oral: Initial: 25 mg once daily; titrate based on tolerance and urinary calcium levels to usual effective dose of 50 to 100 mg/day in 1 to 2 divided doses (Arrabal-Martín 2016; AUA [Pearle 2014]; Curhan 2021; Frassetto 2000; Laerum 1984; Scholz 1982). Some experts suggest twice-daily dosing for doses >25 mg because of the relatively short half-life (Curhan 2021).
Diabetes insipidus, nephrogenic (off-label use):
Note: Consider for use in addition to a low-solute diet to help reduce polyuria (Irwin 2008).
Oral: 25 mg once or twice daily (Irwin 2008).
Edema, refractory (adjunctive to loop diuretic):
Note: Reserve for patients without hypokalemia (Brater 2021).
Oral: Initial: 25 to 100 mg daily in 1 to 2 divided doses; adjust dose based on response and tolerability; maximum daily dose: 200 mg/day (ACCF/AHA [Yancy 2013]). Some experts favor twice-daily dosing (Brater 2021).
Hypertension, chronic (alternative agent):
Note: When a thiazide diuretic is chosen, chlorthalidone or indapamide is preferred (ACC/AHA [Whelton 2018]; Mann 2021). For patients who warrant combination therapy (blood pressure ≥20/10 mm Hg above goal or suboptimal response to initial monotherapy), may use in combination with another appropriate agent (eg, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, dihydropyridine calcium channel blocker) (ACC/AHA [Whelton 2018]). However, some experts prefer regimens that do not include thiazide diuretics for combination therapy (Mann 2021).
Oral: Initial: 12.5 to 25 mg once daily; evaluate response after ~2 to 4 weeks and titrate dose, as needed, up to 50 mg once daily (ACC/AHA [Whelton 2018]; Mann 2021); some experts do not recommend doses higher than 25 mg/day because of greater adverse effects without additional antihypertensive effect; if additional blood pressure control is needed, consider combination therapy. Patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication titration within 1 week (Jamerson 2008; Mann 2021; Ojji 2019).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
CrCl ≥10 mL/minute: No dosage adjustment necessary. The diuretic effect is diminished with CrCl <30 mL/minute, but small, short-term studies suggest hypertensive benefit may be preserved (Agarwal 2012; Dussol 2005; Dussol 2012; KDIGO 2012; Knauf 1995; Kramer 2019; Sinha 2016). Switching to a loop diuretic may be considered if BP is no longer controlled or if management of fluid overload is required (KDIGO 2012).
CrCl <10 mL/minute: Use not recommended due to lack of efficacy (Sinha 2019; manufacturer's labeling).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Bennett 1977); use not recommended due to lack of efficacy (Bennett 1977; Sinha 2019).
Peritoneal dialysis: Use not recommended due to lack of efficacy (Sinha 2019).
CRRT: In general, use not recommended; fluid management can be more effectively managed using CRRT ultrafiltration (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): In general, use not recommended; fluid management can be more effectively managed using PIRRT ultrafiltration (expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling. However, use with caution and monitor for precipitation of hepatic coma.
(For additional information see "Hydrochlorothiazide: Pediatric drug information")
Bronchopulmonary dysplasia (BPD): Limited data available; efficacy results variable. Note: Although the benefits of diuretic therapy in management of BPD are variable (eg, optimal duration of therapy, impact on pulmonary endpoints), diuretics continue to be used in clinical practice (Slaughter 2013).
Infants: Oral: 3 to 4 mg/kg/day in 2 divided doses (Albersheim 1989; Engelhardt 1989).
Central diabetes insipidus: Very limited data available: Infants and Children <3 years: Oral: 1 to 2 mg/kg/day. Dosing based on retrospective descriptive analysis (n=13, age range: 0.5 to 27 months) (Al Nofal 2015).
Edema (diuresis) (van der Vorst 2006; manufacturer's labeling):
Infants <6 months: Oral: 1 to 2 mg/kg/day in 1 to 2 divided doses; some infants may require 3 mg/kg/day in 2 divided doses; maximum daily dose: 37.5 mg/day.
Infants ≥6 months and Children <2 years: Oral: 1 to 2 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 37.5 mg/day.
Children ≥2 years: Oral: 1 to 2 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 100 mg/day.
Adolescents: Limited data available: Oral: 1 to 2 mg/kg/day in 1 to 2 divided doses. Note: Maximum adult daily dose recommended for heart failure-related edema: 200 mg/day (ACCF/AHA [Yancy 2013]).
Hypertension:
Infants <6 months: Oral: 1 to 2 mg/kg/day in 1 to 2 divided doses; some infants may require 3 mg/kg/day in 2 divided doses; maximum daily dose: 37.5 mg/day (AAP [Flynn 2017]; manufacturer's labeling).
Infants ≥6 months and Children <2 years: Oral: 1 to 2 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 37.5 mg/day (AAP [Flynn 2017]; manufacturer's labeling).
Children ≥2 years: Oral: 1 to 2 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 100 mg/day (manufacturer's labeling); a lower maximum dose of 37.5 mg/day has been suggested by recent guidelines (AAP [Flynn 2017]).
Adolescents: Limited data available: Oral: Initial: 1 mg/kg/day once daily; may increase to maximum daily dose: 3 mg/kg/day or 50 mg/day, whichever is lower (NHBPEP 2004; NHLBI 2011).
Hypercalciuria: Limited data available: Infants, Children, and Adolescents: Oral: Initial: 1 to 2 mg/kg/day in 1 to 2 divided doses; lower initial doses of 0.5 mg/kg/day has been reported in infants and children; titrate until goal urinary calcium excretion goals reached and symptoms resolve; treatment usually continued for 1 year; usual adult dose: 25 to 100 mg/day (Choi 2011; Copelovitch 2012; Naseri 2011; Santos-Victoriano 1998).
Nephrogenic diabetes insipidus; congenital: Limited data available: Infants, Children, and Adolescents: Oral: Usual dosage range: 1 to 3 mg/kg/day in combination with amiloride. Dosing based on a retrospective descriptive analysis (n=30, age range: 1 month to 40 years), and a retrospective analysis (n=10, median age at diagnosis: 1.6 years [age range: 0.16 to 6.33 years]), and a pediatric case series (n=4) in patients receiving hydrochlorothiazide in combination with amiloride (Caletti 2014; Kirchlechner 1999; Van Lieburg 1999). In adults, usual dose is 25 mg once or twice daily (Irwin 2008).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function: Infants, Children, and Adolescents:
There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended (Aronoff 2007):
GFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR <30 mL/minute/1.73 m2: Use not recommended; use is contraindicated with anuria.
Hemodialysis, intermittent: Not dialyzable (Bennett 1977); there are no dosage adjustments provided in the manufacturer's labeling; use not recommended (Aronoff 2007).
Peritoneal dialysis: There are no dosage adjustments provided in the manufacturer's labeling; use not recommended (Aronoff 2007).
There are no dosage adjustments provided in the manufacturer's labeling; however, use with caution and monitor for precipitation of hepatic coma.
Oral: Initial: 12.5 mg once daily; titrate as necessary in increments of 12.5 mg. Minimal increase in response and more electrolyte disturbances are seen with doses >50 mg daily.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Microzide: 12.5 mg [DSC]
Generic: 12.5 mg
Tablet, Oral:
Generic: 12.5 mg, 25 mg, 50 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Urozide: 25 mg, 50 mg, 100 mg [contains fd&c yellow #6 aluminum lake]
Generic: 12.5 mg, 25 mg, 50 mg, 100 mg
Oral: Administer early in day to avoid nocturia. Take the last dose of multiple doses no later than 6 PM unless instructed otherwise.
Oral: May administer with or without food; administer early in day to avoid nocturia; if multiple daily dosing, the last dose should not be administered later than 6 PM unless instructed otherwise.
Edema, refractory: Treatment of edema due to heart failure, various forms of renal dysfunction (eg, nephrotic syndrome, acute glomerulosclerosis, chronic renal failure), or corticosteroid or estrogen therapy. Note: Loop diuretics are typically favored, but hydrochlorothiazide may be used as an adjunctive agent for refractory edema (Brater 2011).
Hypertension, chronic: Management of mild to moderate hypertension.
Calcium nephrolithiasis, prevention; Diabetes insipidus, nephrogenic
HCTZ is an error-prone abbreviation (mistaken as hydrocortisone)
HydroCHLOROthiazide may be confused with hydrALAZINE, hydrocortisone, hydrOXYzine, Viskazide
Microzide may be confused with Maxzide, Micronase
Esidrex [multiple international markets] may be confused with Lasix brand name for furosemide [US, Canada, and multiple international markets]
Esidrix [Germany] may be confused with Lasix brand name for furosemide [US, Canada, and multiple international markets]
Beers Criteria: Diuretics are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2019]).
Skin photosensitivity may occur with hydrochlorothiazide. Cumulative use may increase the risk for squamous cell carcinoma (SCC) of skin (lip) and basal cell carcinoma (BCC) of skin (Ref).
Mechanism: Skin photosensitivity: Non-dose-related; idiosyncratic. Diuretics reduce the minimum UV radiation needed to produce a sunburn-like response, increasing the risk of phototoxicity and potentially photocarcinogenesis (Ref). SCC and BCC: Dose- and time-related (Ref); risk may be mediated through skin photosensitivity (Ref).
Onset: SCC/BCC: Delayed (Ref)
Risk factors:
SCC/BCC:
• Cumulative use (ie, ≥5 years) (Ref)
Reversible hypokalemia, hypomagnesemia, hypercalcemia, and hyponatremia may occur with hydrochlorothiazide and may increase the risk of arrhythmias. Development of electrolyte disturbances may be minimized when used in combination with other electrolyte-sparing antihypertensives (eg, angiotensin-converting enzyme, angiotensin receptor blockers, or aldosterone inhibitors) (Ref).
Mechanism: Dose-related; related to the pharmacologic action. Thiazide diuretics block the NaCl cotransporter in the distal convoluted tubule, leading to decreased reabsorption of sodium and chloride and increased delivery of sodium to the collecting duct, which leads to increased potassium wasting. Diluting capacity of the kidney is also impaired, leading to decreased magnesium and increased calcium concentrations (Ref).
Onset: Varied; hypokalemia generally occurs within 2 weeks of initiation (Ref). Hyponatremia onset may range from 2 weeks to 10 years after treatment initiation (Ref).
Risk factors:
• High doses (>25 mg/day) (Ref) or concurrent loop diuretic therapy (Ref)
• Hypokalemia: GI losses (eg, vomiting, diarrhea) (Ref)
• Hypomagnesemia: Heart failure, poor magnesium intake, high alcohol intake (Ref)
• Hyponatremia: Increased water intake (Ref); older patients, females (Ref)
• Hypercalcemia: Older patients, females (Ref)
Hydrochlorothiazide may cause hyperuricemia and precipitate gout or gouty arthritis in susceptible individuals (Ref).
Mechanism: Dose- and time-related; related to the pharmacologic action. Diuretics increase reabsorption of uric acid in the proximal tubule, reducing urinary excretion, increasing the risk of hyperuricemia and gout (Ref). Volume contraction with use of diuretics may also contribute (Ref).
Onset: Rapid; hyperuricemia and gout generally occur within the first few days of treatment initiation (Ref) but may occur up to one year after treatment initiation (Ref).
Risk factors:
• High doses (Ref)
• Increased duration of therapy (Ref)
• Personal or family history of gout (Ref)
Hypersensitivity reactions (immediate and delayed): Hypersensitivity reactions, both immediate and delayed, have been reported (Ref). Delayed hypersensitivity reactions range from maculopapular skin rash to rare severe cutaneous adverse reactions, including acute generalized exanthematous pustulosis (Ref). Other hypersensitivity reactions include interstitial nephritis and interstitial pneumonitis (Ref). Additionally, hydrochlorothiazide has rarely been associated with noncardiogenic pulmonary edema (Ref).
Mechanism: Immediate hypersensitivity reactions: Non-dose-related; immunologic (ie, IgE-mediated, with specific antibodies formed against a drug allergen following initial exposure) (Ref). Delayed hypersensitivity reactions: Non-dose-related; immunologic (ie, involving a T-cell mediated drug-specific immune response) (Ref). Noncardiogenic pulmonary edema: Unknown; various proposed mechanisms including immunologic (Ref), idiosyncratic (Ref), and mast cell or complement activation (Ref).
Onset: Immediate hypersensitivity reactions: Rapid; generally occur within 1 hour of administration but may occur up to 6 hours after exposure (Ref). Delayed hypersensitivity reactions: Varied; typically occur days to 6 weeks after drug exposure, but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref). Noncardiogenic pulmonary edema: Rapid; occurs within 10 to 150 minutes (Ref); upon rechallenge, symptoms develop more rapidly and are often severe (Ref).
Risk factors:
• Cross-reactivity: Limited published information regarding possible cross-reactivity between hydrochlorothiazide and other sulfonamides (Ref). Cross-reactivity due to antibody production (anaphylaxis) is unlikely to occur with nonantibiotic sulfonamides and antibiotic sulfonamides (Ref). Cross-reactivity among thiazide diuretics is unknown.
Sulfa derivatives, such as hydrochlorothiazide, may rarely cause acute transient myopia and acute angle-closure glaucoma which is generally reversible (Ref).
Mechanism: Non-dose-related; idiosyncratic (ie, suggested to involve ciliochoroidal effusion and anterior rotation of the ciliary body, leading to myopic shift and angle closure) (Ref). Hyponatremia may also play a role (Ref).
Onset: Varied; reported to occur between 2 days and 7 years after initiation (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are dose-related, with the majority occurring with doses ≥25 mg.
Frequency not defined:
Cardiovascular: Hypersensitivity angiitis, hypotension (including orthostatic)
Dermatologic: Alopecia, skin rash, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Glycosuria, hypomagnesemia
Gastrointestinal: Abdominal cramps, anorexia, constipation, diarrhea, gastric irritation, nausea, vomiting
Hematologic & oncologic: Aplastic anemia, thrombocytopenia
Hypersensitivity: Anaphylaxis
Nervous system: Dizziness, headache, paresthesia, restlessness, vertigo
Neuromuscular & skeletal: Asthenia, muscle spasm
Ophthalmic: Blurred vision (transient), xanthopsia
Renal: Acute kidney injury
Miscellaneous: Fever
Postmarketing:
Dermatologic: Acute generalized exanthematous pustulosis (Reap 2019), psoriasis (Song 2021), skin photosensitivity (Rosenthal 2019), Stevens-Johnson syndrome (Assad 1978)
Endocrine & metabolic: Hypercalcemia (rare: <1%) (Desai 2010; Wermers 2007), hyperglycemia (Zhang 2016), hyperuricemia (more frequent: ≥4% to <10%) (McAdams DeMarco 2012; Palmer 2011), hypochloremic alkalosis (Pela 2008), hypokalemia (Schell 2019), hyponatremia (common: ≥10%) (Leung 2011; Sardar 2015)
Gastrointestinal: Pancreatitis (Spera 2016), sialadenitis (Thomopoulos 2018)
Genitourinary: Impotence (Handler 2011)
Hematologic & oncologic: Agranulocytosis (Chrein 1962), basal cell carcinoma of skin (more frequent: ≥4% to <10%) (Pedersen 2018), hemolytic anemia (Shirey 1988), leukopenia (Sosenko 2019), malignant neoplasm of lip (Friedman 2012), purpuric disease (Okafor 1986), squamous cell carcinoma of skin (common: ≥10%) (Pottegård 2017)
Hepatic: Cholestatic hepatitis (Taglietti 2010)
Hypersensitivity: Angioedema (Ruscin 2006)
Neuromuscular & skeletal: Systemic lupus erythematosus (Sosenko 2019)
Ophthalmic: Acute angle-closure glaucoma (rare: <1%) (Chen 2014), myopia (rare: <1%) (Roh 2011)
Renal: Interstitial nephritis (Magil 1980)
Respiratory: Interstitial pneumonitis (Biron 1991), noncardiogenic pulmonary edema (Goetschlalckx 2007)
Hypersensitivity to hydrochlorothiazide, any component of the formulation, or sulfonamide-derived drugs; anuria
Note: Although some product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail.
Canadian labeling: Additional contraindications (not in US labeling): Increasing azotemia and oliguria during treatment of severe progressive renal disease; breast-feeding
Documentation of allergenic cross-reactivity for thiazide-related diuretics is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.
Disease-related concerns:
• Adrenal insufficiency: Avoid use of diuretics for treatment of elevated blood pressure in patients with primary adrenal insufficiency (Addison disease). Adjustment of glucocorticoid/mineralocorticoid therapy and/or use of other antihypertensive agents is preferred to treat hypertension (Bornstein 2016; Inder 2015).
• Ascites due to cirrhosis: Use with extreme caution or avoid hydrochlorothiazide in the management of ascites due to cirrhosis; may lead to rapid development of hyponatremia when used in combination with spironolactone and furosemide (AASLD [Runyon 2012]).
• Bariatric surgery: Dehydration: Avoid diuretics in the immediate postoperative period after bariatric surgery; electrolyte disturbances and dehydration may occur. Diuretics may be resumed, if indicated, once oral fluid intake goals are met (Ziegler 2009).
• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.
• Hepatic impairment: Use with caution in patients with severe hepatic dysfunction; in progressive or severe liver disease, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy/coma.
• Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported.
• Parathyroid disease: Thiazide diuretics reduce calcium excretion; pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed with prolonged use; should be discontinued prior to testing for parathyroid function.
• Renal impairment: Cumulative effects may develop, including azotemia, in patients with impaired renal function. Avoid in severe renal disease (ineffective).
• Systemic lupus erythematosus (SLE): May cause SLE exacerbation or activation.
Special populations:
• Surgical patients: If given the morning of surgery, hydrochlorothiazide may render the patient volume depleted and blood pressure may be labile during general anesthesia.
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
None known.
Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Allopurinol: Thiazide and Thiazide-Like Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Anticholinergic Agents: May increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arsenic Trioxide: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of Arsenic Trioxide. Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Arsenic Trioxide. Management: When possible, avoid concurrent use of arsenic trioxide with drugs that can cause electrolyte abnormalities, such as the thiazide and thiazide-like diuretics. Risk D: Consider therapy modification
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benazepril: HydroCHLOROthiazide may enhance the hypotensive effect of Benazepril. HydroCHLOROthiazide may enhance the nephrotoxic effect of Benazepril. Benazepril may decrease the serum concentration of HydroCHLOROthiazide. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide and Thiazide-Like Diuretics. The diuretic response is likewise decreased. Management: Consider separating administraton of bile acid sequestrants and thiazide diuretics by at least 4 hours. Monitor for decreased therapeutic effects of thiazide diuretics if coadministered with a bile acid sequestrant. Risk D: Consider therapy modification
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Calcium Salts: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
CarBAMazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy
Cardiac Glycosides: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Cyclophosphamide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Risk C: Monitor therapy
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be increased. Risk C: Monitor therapy
Diazoxide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Diazoxide. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dichlorphenamide: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Dichlorphenamide. Risk C: Monitor therapy
Dofetilide: HydroCHLOROthiazide may enhance the QTc-prolonging effect of Dofetilide. HydroCHLOROthiazide may increase the serum concentration of Dofetilide. Risk X: Avoid combination
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Ipragliflozin: May enhance the adverse/toxic effect of Thiazide and Thiazide-Like Diuretics. Specifically, the risk for intravascular volume depletion may be increased. Risk C: Monitor therapy
Ivabradine: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Ivabradine. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Levosulpiride: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Levosulpiride. Risk X: Avoid combination
Licorice: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Lithium: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Lithium. Management: Reduce the lithium dose if coadministered with thiazide or thiazide-like diuretics. Monitor serum lithium levels during coadministration with thiazide and thiazide-like diuretics. Risk D: Consider therapy modification
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Mecamylamine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Mecamylamine. Management: Consider avoiding the use of mecamylamine and thiazide diuretics. If combined, mecamylamine prescribing information suggests reducing the mecamylamine dose by 50% in order to avoid excessive hypotension. Risk D: Consider therapy modification
Methenamine: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Methenamine. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the hypercalcemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Multivitamins/Minerals (with ADEK, Folate, Iron). Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Multivitamins/Minerals (with AE, No Iron). Specifically, thiazide diuretics may decrease the excretion of calcium, and continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Thiazide and Thiazide-Like Diuretics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Opioid Agonists: May enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
OXcarbazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Promazine: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Promazine. Risk X: Avoid combination
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Reboxetine: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification
Topiramate: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (eg, hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Risk D: Consider therapy modification
Toremifene: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Toremifene. Risk C: Monitor therapy
Valsartan: HydroCHLOROthiazide may enhance the hypotensive effect of Valsartan. Valsartan may increase the serum concentration of HydroCHLOROthiazide. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin D Analogs: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy
Hydrochlorothiazide crosses the placenta (Beerman 1980).
Maternal use may cause fetal or neonatal jaundice, thrombocytopenia, or other adverse events observed in adults.
Use of thiazide diuretics to treat edema during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in the nonpregnant patient); monitor.
Chronic maternal hypertension is associated with adverse events in the fetus/infant. The risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death may be increased with chronic hypertension in pregnancy. Actual risks may be related to duration and severity of maternal hypertension. Diuretics are considered second-line therapy for treating chronic hypertension in pregnancy (ACOG 203 2019).
The treatment of edema associated with chronic heart failure during pregnancy is similar to that of nonpregnant patients. Use of thiazide diuretics may be considered but use with caution due to the potential reduction in placental blood flow. Patients diagnosed after delivery can be treated according to heart failure guidelines (ESC [Bauersachs 2016]; ESC [Regitz-Zagrosek 2018]).
Hydrochlorothiazide is present in breast milk.
The relative infant dose (RID) of hydrochlorothiazide is 0.6% to 1.2% when compared to an infant therapeutic dose of 1 to 2 mg/kg/day.
In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).
The RID of hydrochlorothiazide was calculated using a mean milk concentration of 80 ng/mL from a single case report, providing an estimated daily infant dose via breast milk of 0.012 mg/kg/day. This milk concentration was obtained following maternal administration of oral hydrochlorothiazide 50 mg once daily for 3.5 years. Hydrochlorothiazide was not detected in the infant serum (Miller 1982).
Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother. Hydrochlorothiazide is considered compatible with breastfeeding (WHO 2002). However, thiazide diuretics have the potential to decrease milk volume and suppress lactation; use should be avoided when possible (ACOG 203 2019; WHO 2002).
BP, dizziness, lightheadedness; sodium, potassium, BUN, creatinine; skin to assess for photosensitivity, skin cancer; visual acuity, ocular pain.
BP goals: May vary depending on clinical condition, different clinical practice guidelines, and expert opinion. Refer to clinical practice guidelines for specific treatment goals.
Inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions
Onset of action: Diuresis: Infants: 2 to 6 hours (Chemtob 1989); Adults: ~2 hours.
Peak effect: ~4 hours.
Duration: Infants: 8 hours (Chemtob 1989); Adults: 6 to 12 hours.
Absorption: Well absorbed; absorption is reduced in patients with CHF.
Distribution: 3.6 to 7.8 L/kg (correlates with dose administered and concentration achieved).
Protein binding: ~40% to 68%.
Metabolism: Not metabolized.
Bioavailability: 65% to 75%.
Half-life elimination: ~6 to 15 hours.
Time to peak: ~1 to 5 hours.
Excretion: Urine (≥61% as unchanged drug).
Renal function impairment: Hydrochlorothiazide plasma concentration is increased and the half-life is prolonged.
Capsules (hydroCHLOROthiazide Oral)
12.5 mg (per each): $0.42 - $0.43
Tablets (hydroCHLOROthiazide Oral)
12.5 mg (per each): $0.17 - $0.82
25 mg (per each): $0.08
50 mg (per each): $0.13 - $0.16
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