Pronunciation: lye-SIN-oh-pril/HYE-droe-KLOR-oh-THYE-a-zide
Class: Antihypertensive combination

Trade Names

Prinzide 10/12.5 mg
- Tablets, oral lisinopril 10 mg/hydrochlorothiazide 12.5 mg

Prinzide 20/12.5 mg
- Tablets, oral lisinopril 20 mg/hydrochlorothiazide 12.5 mg

Zestoretic 10/12.5 mg
- Tablets, oral lisinopril 10 mg/hydrochlorothiazide 12.5 mg

Zestoretic 20/12.5 mg
- Tablets, oral lisinopril 20 mg/hydrochlorothiazide 12.5 mg

Zestoretic 20/25 mg
- Tablets, oral lisinopril 20 mg/hydrochlorothiazide 25 mg

Pharmacology

Lisinopril

Competitively inhibits ACE, preventing the conversion of angiotensin I to angiotensin II, reversing the potassium loss associated with the diuretic.

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Hydrochlorothiazide

Increases chloride, sodium, and water excretion by interfering with transport of sodium ions across renal tubular epithelium.

Indications and Usage

For the treatment of hypertension.

Contraindications

History of angioedema related to previous treatment with an ACE inhibitor; hereditary or idiopathic angioedema; anuria; hypersensitivity to sulfonamide-derived drugs or hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO Usual daily dose is lisinopril 10 to 80 mg/hydrochlorothiazide 12.5 to 50 mg. Allow 2 to 3 wk to elapse before adjusting the hydrochlorothiazide dose (max, lisinopril 80 mg/hydrochlorothiazide 50 mg).

Renal Function Impairment

Not recommended when CrCl is less than 30 mL/min.

General Advice

• Administer with or without food.
• The combination may be substituted for the titrated individual components.
• Not indicated for initial therapy of hypertension.

Storage/Stability

Store between 59° and 86°F. Protect from excessive light and moisture.

Drug Interactions

No drug interaction studies have been conducted between lisinopril/hydrochlorothiazide and other drugs. The following interactions are based on drug interactions involving each component of the lisinopril/hydrochlorothiazide combination.

Lisinopril Aldosterone blockers (eg, eplerenone)

May cause serious hyperkalemia, possibly with cardiac arrhythmias. Monitor potassium level periodically and reduce dose of aldosterone blocker if needed.

Aliskiren

May decrease renal excretion of potassium. Closely monitor serum potassium.

Angiotensin II receptor antagonists (eg, valsartan)

Increased risk of renal dysfunction and hyperkalemia. Closely monitor renal function and serum potassium.

Clozapine

May cause excessive decreases in BP and syncope. Consider lower starting dosage of clozapine.

Cyclooxygenase 2 inhibitors (eg, celecoxib)

May result in deterioration of renal function, including acute renal failure. Monitor renal function, particularly in patients who are elderly or volume-depleted, or those with impaired renal function.

Cyclosporine

Renal failure has been reported with cyclosporine and ACE inhibitor administration. If renal dysfunction occurs, it may be necessary to stop one or both agents.

Gold

Nitroid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) may occur in patients using injectable gold (sodium aurothiomalate).

Ketorolac (nasal)

May cause decreased antihypertensive effects. Monitor BP closely. If BP control deteriorates, consider stopping ketorolac (nasal).

mTOR inhibitors (eg, everolimus, sirolimus)

Increased risk of angioedema ranging from minor facial edema to life-threatening mouth and throat swelling may occur. If an interaction is suspected, stop one or both drugs.

Pergolide

May cause hypotension. Start with lower doses of pergolide and monitor BP closely. If BP falls, dosage reduction may be needed.

Phenothiazines

May produce a synergistic hypotensive effect with postural syncope. Monitor BP (supine and standing) and adjust dosage of antihypertensive as needed.

Potassium preparations, potassium-sparing diuretics

May significantly increase serum potassium levels. Hyperkalemia, possibly with cardiac arrhythmias or arrest, may occur. Closely monitor serum potassium concentrations.

Salicylates (eg, aspirin, bismuth salicylate)

Hypotensive effects may be decreased. Adjust dosage of antihypertensive as needed. May need to stop salicylates if BP control or renal function deteriorates.

Tizanidine

May cause severe hypotension. Monitor BP.

Trimethoprim

May cause hyperkalemia and possibly cardiac arrhythmias. Closely monitor serum potassium.

Hydrochlorothiazide Adrenocorticotropic hormones, corticosteroids

Electrolyte depletion may be intensified, particularly hypokalemia. Laboratory monitoring is warranted.

Alcohol, barbiturates, narcotics

Potentiation of orthostatic hypotension may occur. Monitor BP.

Antihypertensive agents

Additive or potentiation of hypotension effects. Closely monitor BP.

Antineoplastic agents (eg, cyclophosphamide)

Hydrochlorothiazide may prolong antineoplastic-induced myelosuppression. Use with caution.

Cholestyramine, colestipol resins

Hydrochlorothiazide absorption may be impaired. Single doses of cholestyramine or colestipol resins bind hydrochlorothiazide, reducing GI absorption up to 85% and 43%, respectively. Separate the administration times by as much as possible.

Diazoxide

The pharmacologic effects of both drugs may be increased. Hyperglycemia, hyperuricemia, and hypotension may occur. Closely monitor BP, blood glucose, and serum uric acid.

Digoxin

Hydrochlorothiazide-induced electrolyte disturbances may predispose to digitalis-induced arrhythmias. Measure plasma concentrations of potassium and magnesium; supplement low levels. Prevent further losses with dietary management.

Dofetilide

Dofetilide plasma concentrations may be increased. Prolongation of the QT interval may occur, increasing the risk of torsades de pointes. Coadministration of hydrochlorothiazide and dofetilide is contraindicated.

Hypoglycemic agents, oral (eg, sulfonylureas)

Hydrochlorothiazide may increase fasting blood glucose and decrease insulin secretion. The effect of oral hypoglycemic agents and insulin may be decreased. Monitor blood glucose and adjust the hypoglycemic dose as needed.

Insulin

Hydrochlorothiazide may increase fasting blood glucose and decrease insulin secretion. The effect of insulin may be decreased. Monitor blood glucose and adjust the insulin dose as needed.

Lithium

Lithium clearance may be decreased, increasing lithium concentrations and the risk of lithium toxicity. Lithium generally should not be given with diuretics.

Loop diuretics (eg, furosemide)

May cause diuresis and serious electrolyte abnormalities. Monitor for dehydration and electrolyte abnormalities during combined therapy.

Nondepolarizing muscle relaxants (eg, tubocurarine)

Possible increased responsiveness to the muscle relaxant due to diuretic-induced hypokalemia. If hypokalemia cannot be corrected, a lower dosage of nondepolarizing muscle relaxants may be needed.

NSAIDs (eg, ibuprofen, indomethacin)

The diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide may be reduced. Monitor BP and the diuretic response. Additional monitoring of renal function may be needed in elderly or volume-depleted patients or in those who have decreased renal function.

Pressor amines (eg, norepinephrine)

Response to pressor amines may be decreased. Use with caution.

Tretinoin

The risk of phototoxicity may be increased if these agents are coadministered. Avoid coadministration.

Adverse Reactions

Cardiovascular

Orthostatic effects (3%); hypotension (1%); orthostatic hypotension, palpitation, syncope (up to 1%).

CNS

Dizziness (8%); headache (5%); fatigue (4%); asthenia, paresthesia (2%); decreased libido, depression, somnolence, vertigo (up to 1%).

Dermatologic

Rash (1%); diaphoresis, flushing, pruritus, skin inflammation (up to 1%).

EENT

Blurred vision, otalgia, tinnitus (up to 1%).

GI

Diarrhea (3%); nausea (2%); dyspepsia, vomiting (1%); abdominal pain, constipation, dry mouth, GI cramps, heartburn (up to 1%).

Genitourinary

Impotence (1%); UTI (up to 1%).

Hematologic

Decreased hemoglobin and hematocrit.

Hepatic

Elevated liver enzymes and/or serum bilirubin.

Metabolic

Hypercalcemia; hyperglycemia; hyperuricemia, hypochloremic alkalosis; hypokalemia; hypomagnesemia; hyponatremia; increased triglycerides and cholesterol levels.

Respiratory

Cough (4%); upper respiratory tract infection (2%); allergic rhinitis, bronchitis, chronic sinusitis, common cold, dyspnea, influenza, nasal congestion, pharyngeal discomfort, pharyngeal pain, pulmonary congestion, (up to 1%).

Miscellaneous

Muscle cramps (2%); back pain, back strain, chest discomfort, chest pain, cold foot, fever, knee pain, myalgia, shoulder pain, trauma, virus infection (up to 1%); angioedema.

Precautions

Warnings When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, discontinue therapy as soon as possible.

Monitor Observe all patients for signs of fluid or electrolyte imbalance (eg, hyponatremia, hypochloremic, alkalosis, hypokalemia, hyperkalemia, hypomagnesemia). Periodically determine serum electrolytes at appropriate intervals, including potassium, BUN, and serum creatinine, especially when therapy is initiated or dosage adjusted. Periodically monitor WBC in patients with collagen vascular disease and renal disease. Monitor blood sugar in patients with diabetes when lisinopril/hydrochlorothiazide is started or the dose is changed. Monitor and record BP and pulse.

Pregnancy

Category D (second and third trimesters); Category C (first trimester). Lisinopril can cause fetal and neonatal morbidity and death when administered to pregnant women. Do not use during pregnancy.

Lactation

Undetermined (lisinopril); excreted in breast milk (hydrochlorothiazide).

Children

Safety and efficacy not established.

Elderly

Hydrochlorothiazide is excreted by the kidneys and the risk of toxic reactions may be greater in patients with renal impairment.

Hypersensitivity

Life-threatening anaphylactoid reactions have been reported with ACE inhibitors. Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

Renal Function

Not recommended in severe renal impairment. Use with caution in mild to moderate renal impairment.

Hepatic Function

Use with caution. Minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients treated with lisinopril. This may occur at any time during treatment. Intestinal angioedema has also been reported with ACE inhibitors. Black patients have a higher incidence of angioedema compared with nonblack patients.

Aortic stenosis/hypertrophic cardiomyopathy

Use with caution in patients with obstruction in the outflow tract of the left ventricle.

Cough

Persistent nonproductive cough has been reported with all ACE inhibitors; the cough almost always resolves after discontinuation of therapy.

Diabetes

Dosage adjustment of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur and diabetes mellitus may manifest during administration.

Electrolyte imbalance

Hyperkalemia, hypokalemia, hypercalcemia, hypochloremic alkalosis, hyponatremia, and hypomagnesemia may occur. Hyperkalemia is more likely to occur in patients with renal impairment or diabetes, elderly patients, or severely ill patients.

Hematologic effects

Neutropenia and bone marrow suppression may occur, and are seen more frequently in patients with renal impairment, especially if they also have collagen vascular disease.

Hepatic effects

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis.

Hyperuricemia

May occur or frank gout may be precipitated.

Hypotension/Syncope

Excessive hypotension may occur, especially in severely salt- or volume-depleted patients or those with severe CHF. Syncope has been reported.

Lipid effects

Increases in cholesterol and triglyceride levels may occur.

Ocular effects

Hydrochlorothiazide can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma within hours to weeks of drug initiation.

Renal effects

In patients with severe CHF whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with lisinopril may be associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death. Increases in BUN and serum creatinine may occur.

Postsympathectomy

The antihypertensives effects may be enhanced in the postsympathectomy patient.

Surgery/Anesthesia

Risk of hypotension may be may be increased; if hypotension occurs, it can be corrected by volume expansion.

Systemic lupus erythematosus

May exacerbate or activate systemic lupus erythematosus.

Overdosage

Symptoms

Dehydration, electrolyte imbalance (eg, hypokalemia, hypochloremia, hyponatremia), hypotension.

Patient Information

• Inform patients that angioedema, including laryngeal edema, may occur at any time during treatment. Advise patients to immediately report any signs or symptoms suggesting angioedema (eg, swelling of the face, extremities, eyes, lips, tongue; difficulty in swallowing or breathing) and to stop taking the medication until they have consulted with their health care provider.
• Caution patients to report light-headedness, especially during the first few days of therapy. If syncope occurs, advise patients to discontinue the medication until they have consulted their health care provider.
• Caution all patients that excessive perspiration, dehydration, vomiting, or diarrhea may lead to an excessive fall in BP because of reduction in fluid volume.
• Instruct patients not to use salt substitutes containing potassium without consulting their health care provider.
• Inform patients to promptly report any indication of infection (eg, sore throat, fever), which may be a sign of leukopenia/neutropenia.
• Inform women of childbearing age about the consequences of exposure to ACE inhibitors during pregnancy. Advise patients to report pregnancies to their health care provider as soon as possible.
• Instruct diabetic patients to monitor blood glucose more frequently when lisinopril/hydrochlorothiazide is started or their dose is changed, and to inform their health care provider of significant changes in readings.
• Caution patients to avoid sudden position changes to prevent orthostatic hypotension and to lie or sit down if they experience dizziness or light-headedness when standing.
• Instruct patients to inform their health care provider if a persistent cough develops while they are taking lisinopril/hydrochlorothiazide.

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