Zestoretic

FDA label

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Titration Do not increase HCTZ component until after 2-3 weeks.

Renal CrCl >30 mL/min/1.73m2 (SCr <=~3 mg/dL): no adjustment; more severe impairment: not recommended (loop diuretics preferred over thiazides)

Hepatic No dose adjustment given; use with caution in impaired hepatic function or progressive liver disease - minor fluid/electrolyte shifts may precipitate hepatic coma; discontinue for jaundice or marked hepatic-enzyme elevation

Not for initial therapy of hypertension

Instructions

• Begin combination only after monotherapy failure (minimizes dose-independent side effects)
• May substitute combination for individually titrated components (replacement therapy)

Available strengths

• tab 12.5/10, 12.5/20, 25/20 mg

Contraindications

• History of angioedema with any ACE inhibitor; hereditary or idiopathic angioedema
• Anuria
• Hypersensitivity to other sulfonamide-derived drugs (HCTZ component)
• Coadministration with a neprilysin inhibitor (sacubitril); do not give within 36 h of switching to/from sacubitril/valsartan
• Coadministration with aliskiren in patients with diabetes

Cautions

• Fetal toxicity (boxed) - discontinue as soon as pregnancy is detected
• Head/neck angioedema (face, extremities, lips, tongue, glottis, larynx) can occur at any time, is more frequent in Black patients and has been fatal - discontinue promptly; airway involvement needs subcutaneous epinephrine 1:1000 (0.3-0.5 mL) and airway management
• Intestinal angioedema - consider in patients presenting with abdominal pain on an ACE inhibitor
• Increased angioedema risk with concomitant mTOR inhibitors (temsirolimus, sirolimus, everolimus) or a neprilysin inhibitor
• Life-threatening anaphylactoid reactions during hymenoptera venom desensitization, high-flux membrane dialysis, and LDL apheresis with dextran sulfate
• Excessive hypotension in salt/volume-depleted patients (vigorous diuresis, dialysis); syncope in 0.8% - start under close supervision in severe heart failure, where hypotension may cause oliguria, azotemia, rarely acute renal failure or death; place supine and give IV normal saline if it occurs
• Neutropenia/agranulocytosis and bone marrow depression - consider periodic WBC monitoring in collagen vascular disease and renal disease
• ACE inhibitors rarely cause a syndrome from cholestatic jaundice/hepatitis progressing to fulminant hepatic necrosis - discontinue for jaundice or marked hepatic-enzyme elevation
• Hyperkalemia (K+ >5.7 mEq/L in ~1.4% of patients) - risk with renal insufficiency, diabetes, potassium-sparing diuretics, potassium supplements or salt substitutes; monitor serum potassium
• Persistent nonproductive cough that resolves after discontinuation
• Thiazide caution in severe renal disease (may precipitate azotemia; drug may accumulate) and in impaired hepatic function or progressive liver disease (may precipitate hepatic coma)
• Lithium generally should not be given with thiazides - diuretics reduce lithium clearance and add a high risk of lithium toxicity; monitor serum lithium frequently if used with lisinopril
• Electrolyte imbalance: hypokalemia (blunted by lisinopril), hyponatremia, hypochloremic alkalosis, hypomagnesemia; hypokalemia may cause arrhythmia and sensitize the heart to digitalis toxicity - check serum electrolytes periodically
• Hyperuricemia/gout, hyperglycemia and latent diabetes becoming manifest, raised cholesterol and triglycerides with thiazide therapy
• Acute myopia and secondary angle-closure glaucoma (sulfonamide idiosyncratic reaction, hours to weeks after initiation) - discontinue hydrochlorothiazide as rapidly as possible; untreated it can cause permanent vision loss
• Sensitivity reactions with or without a history of allergy or asthma; possible exacerbation or activation of systemic lupus erythematosus
• Hydrochlorothiazide is associated with increased non-melanoma skin cancer (mainly squamous cell) - protect skin from sun and undergo regular skin cancer screening
• Caution with left ventricular outflow tract obstruction (aortic stenosis/hypertrophic cardiomyopathy); hypotension may occur during major surgery or anesthesia - correct with volume expansion

Adverse reactions

• Most frequent: dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%), orthostatic effects (3.2%)
• Also >=1%: diarrhea, nausea, URI, muscle cramps, asthenia, paresthesia, hypotension, vomiting

Pregnancy Boxed - discontinue as soon as pregnancy is detected. Second/third-trimester exposure to RAS-acting drugs reduces fetal renal function and raises fetal/neonatal morbidity and death; oligohydramnios can cause fetal lung hypoplasia and skeletal deformation; neonatal skull hypoplasia, anuria, hypotension, renal failure and death. If no alternative exists, do serial ultrasounds and stop the drug if oligohydramnios appears (unless lifesaving for the mother); observe exposed infants for hypotension, oliguria and hyperkalemia. Thiazides cross the placenta - risk of fetal/neonatal jaundice and thrombocytopenia

Lactation Lisinopril excretion in human milk unknown (present in rat milk); thiazides appear in human milk. Decide whether to discontinue nursing or the drug, considering its importance to the mother.