ZESTORETIC

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZESTORETIC (ZESTORETIC).

How it works

Combination of lisinopril (ACE inhibitor) and hydrochlorothiazide (thiazide diuretic). Lisinopril inhibits angiotensin-converting enzyme, reducing angiotensin II formation, decreasing vasoconstriction and aldosterone secretion. Hydrochlorothiazide inhibits sodium reabsorption in distal convoluted tubule, increasing diuresis and reducing plasma volume.

What the body does with it

Metabolism	Lisinopril: Not metabolized; excreted unchanged in urine. Hydrochlorothiazide: Not extensively metabolized; small amount metabolized via unknown pathways.
Excretion	Lisinopril is excreted unchanged in urine; 100% renal elimination. Hydrochlorothiazide is excreted primarily by the kidney (≥95% as unchanged drug) via tubular secretion.
Half-life	Lisinopril: terminal half-life approximately 12 hours (accumulation half-life 13.8 hours in patients with normal renal function). Hydrochlorothiazide: terminal half-life 5.6–14.8 hours (mean 9.6 hours).
Protein binding	Lisinopril: 25% bound to plasma proteins. Hydrochlorothiazide: 40–68% bound to albumin.
Volume of Distribution	Lisinopril: Vd approximately 1.8 L/kg (suggests extensive extravascular distribution). Hydrochlorothiazide: Vd 0.8–1.0 L/kg.
Bioavailability	Lisinopril: oral bioavailability 25% (range 6–60%). Hydrochlorothiazide: oral bioavailability 65–75%.
Onset of Action	Lisinopril: onset of antihypertensive effect within 1 hour after oral administration. Hydrochlorothiazide: diuresis begins within 2 hours.
Duration of Action	Lisinopril: duration of antihypertensive effect is 24 hours. Hydrochlorothiazide: diuretic effect lasts 6–12 hours.

Classification & Brands

Dosing & administration

Zestoretic (lisinopril/hydrochlorothiazide) is available in fixed-dose combinations. Typical adult dose: 10 mg/12.5 mg, 20 mg/12.5 mg, or 20 mg/25 mg orally once daily. Maximum dose: lisinopril 80 mg/day, hydrochlorothiazide 50 mg/day.

Dosage form	TABLET
Renal impairment	For GFR 30-60 mL/min/1.73 m²: use lower initial doses and titrate cautiously. For GFR <30 mL/min/1.73 m²: contraindicated (hydrochlorothiazide ineffective). Avoid if creatinine clearance <30 mL/min.
Liver impairment	Child-Pugh Class A or B: no specific dose adjustment recommended; use with caution. Child-Pugh Class C: contraindicated (hydrochlorothiazide may precipitate hepatic encephalopathy). No specific Child-Pugh based dosing guidelines established.
Pediatric use	Not recommended for pediatric patients under 18 years due to lack of safety and efficacy data. For hypertension in children, individual components may be used: lisinopril starting 0.07 mg/kg once daily (max 5 mg) titrated to 0.6 mg/kg/day (max 40 mg); hydrochlorothiazide 1-2 mg/kg/day in 1-2 divided doses (max 50 mg/day).
Geriatric use	Start with the lowest available strength (10 mg/12.5 mg) once daily; titrate slowly. Monitor renal function and electrolytes closely. Due to age-related decreased renal function, consider initial dose reduction and careful titration.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ZESTORETIC (ZESTORETIC).

Breastfeeding	Excretion in human milk unknown; alternative agents preferred due to risk of neonatal hypotension and renal impairment. M/P ratio not available.
Teratogenic Risk	First trimester: Limited data suggest potential risk of congenital malformations (renal, cardiac) with ACE inhibitors, but absolute risk is low. Second and third trimesters: Known to cause fetal renal dysfunction, oligohydramnios, skull ossification deficits, hypotension, and anuria; risk of fetal/neonatal death. Contraindicated in second and third trimesters.

Warnings & precautions

■ FDA Black Box Warning

Fetal toxicity: Drugs acting directly on the renin-angiotensin-aldosterone system can cause injury and death to the developing fetus. Discontinue as soon as possible when pregnancy is detected.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to lisinopril, hydrochlorothiazide, or any sulfonamide-derived drug","History of angioedema related to prior ACE inhibitor therapy","Anuria (hydrochlorothiazide)","Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min)","Pregnancy (second and third trimesters)"]

Clinical Precautions

Precautions

["Anaphylactoid reactions (including angioedema) in patients with or without prior ACE inhibitor therapy","Hepatic failure","Neutropenia/agranulocytosis","Impaired renal function (especially in renal artery stenosis)","Electrolyte disturbances (hypokalemia, hyperkalemia, hyponatremia)","Hypotension (volume-depleted patients)","Cough (ACE inhibitor-related)","Sulfonamide sensitivity (hydrochlorothiazide)","Acute angle-closure glaucoma (hydrochlorothiazide)","Exacerbation or activation of systemic lupus erythematosus (thiazides)"]

Clinical Tips & Counseling

Drug interactions

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ZESTORETIC

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZESTORETIC (ZESTORETIC).

How it works

What the body does with it

Metabolism	Lisinopril: Not metabolized; excreted unchanged in urine. Hydrochlorothiazide: Not extensively metabolized; small amount metabolized via unknown pathways.
Excretion	Lisinopril is excreted unchanged in urine; 100% renal elimination. Hydrochlorothiazide is excreted primarily by the kidney (≥95% as unchanged drug) via tubular secretion.
Half-life	Lisinopril: terminal half-life approximately 12 hours (accumulation half-life 13.8 hours in patients with normal renal function). Hydrochlorothiazide: terminal half-life 5.6–14.8 hours (mean 9.6 hours).
Protein binding	Lisinopril: 25% bound to plasma proteins. Hydrochlorothiazide: 40–68% bound to albumin.
Volume of Distribution	Lisinopril: Vd approximately 1.8 L/kg (suggests extensive extravascular distribution). Hydrochlorothiazide: Vd 0.8–1.0 L/kg.
Bioavailability	Lisinopril: oral bioavailability 25% (range 6–60%). Hydrochlorothiazide: oral bioavailability 65–75%.
Onset of Action	Lisinopril: onset of antihypertensive effect within 1 hour after oral administration. Hydrochlorothiazide: diuresis begins within 2 hours.
Duration of Action	Lisinopril: duration of antihypertensive effect is 24 hours. Hydrochlorothiazide: diuretic effect lasts 6–12 hours.

Classification & Brands

Dosing & administration

Dosage form	TABLET
Renal impairment	For GFR 30-60 mL/min/1.73 m²: use lower initial doses and titrate cautiously. For GFR <30 mL/min/1.73 m²: contraindicated (hydrochlorothiazide ineffective). Avoid if creatinine clearance <30 mL/min.
Liver impairment	Child-Pugh Class A or B: no specific dose adjustment recommended; use with caution. Child-Pugh Class C: contraindicated (hydrochlorothiazide may precipitate hepatic encephalopathy). No specific Child-Pugh based dosing guidelines established.
Pediatric use	Not recommended for pediatric patients under 18 years due to lack of safety and efficacy data. For hypertension in children, individual components may be used: lisinopril starting 0.07 mg/kg once daily (max 5 mg) titrated to 0.6 mg/kg/day (max 40 mg); hydrochlorothiazide 1-2 mg/kg/day in 1-2 divided doses (max 50 mg/day).
Geriatric use	Start with the lowest available strength (10 mg/12.5 mg) once daily; titrate slowly. Monitor renal function and electrolytes closely. Due to age-related decreased renal function, consider initial dose reduction and careful titration.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ZESTORETIC (ZESTORETIC).

Breastfeeding	Excretion in human milk unknown; alternative agents preferred due to risk of neonatal hypotension and renal impairment. M/P ratio not available.
Teratogenic Risk	First trimester: Limited data suggest potential risk of congenital malformations (renal, cardiac) with ACE inhibitors, but absolute risk is low. Second and third trimesters: Known to cause fetal renal dysfunction, oligohydramnios, skull ossification deficits, hypotension, and anuria; risk of fetal/neonatal death. Contraindicated in second and third trimesters.

Warnings & precautions

■ FDA Black Box Warning

Fetal toxicity: Drugs acting directly on the renin-angiotensin-aldosterone system can cause injury and death to the developing fetus. Discontinue as soon as possible when pregnancy is detected.