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Lisinopril

Pronunciation

Pronunciation

(lyse IN oh pril)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Prinivil: 5 mg, 10 mg, 20 mg [scored]

Zestril: 2.5 mg

Zestril: 5 mg [scored]

Zestril: 10 mg, 20 mg, 30 mg, 40 mg

Generic: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg

Brand Names: U.S.

  • Prinivil
  • Zestril

Pharmacologic Category

  • Angiotensin-Converting Enzyme (ACE) Inhibitor
  • Antihypertensive

Pharmacology

Competitive inhibitor of angiotensin-converting enzyme (ACE); prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion; a CNS mechanism may also be involved in hypotensive effect as angiotensin II increases adrenergic outflow from CNS; vasoactive kallikreins may be decreased in conversion to active hormones by ACE inhibitors, thus reducing blood pressure

Absorption

Unaffected by food

Metabolism

Not metabolized

Excretion

Primarily urine (as unchanged drug)

Onset of Action

1 hour; Peak effect: Hypotensive: Oral: ~6 hours

Time to Peak

~7 hours

Duration of Action

24 hours

Half-Life Elimination

12 hours

Special Populations: Renal Function Impairment

Decreased elimination when glomerular filtration rate is 30 mL/min or less. With greater impairment, peak and trough lisinopril levels increase, time to peak concentration increases, and time to attain steady state is prolonged.

Special Populations: Elderly

Higher (~ doubled) blood levels and area under the plasma concentration time curve (AUC) than younger patients.

Special Populations: Race

Black patients with hypertension had a smaller response to monotherapy of ACE inhibitor.

Special Populations Note

CHF (New York Heart Association class II through IV)

Bioavailability decreased to 16% and Vd is slightly smaller.

Use: Labeled Indications

Acute myocardial infarction: Treatment of acute myocardial infarction (MI) within 24 hours in hemodynamically-stable patients to improve survival

Heart failure: Adjunctive therapy in treatment systolic of heart failure (HF)

Hypertension: Treatment of hypertension, either alone or in combination with other antihypertensive agents in adult and pediatric patients 6 years and older

Guideline recommendations:

Heart failure: The ACCF/AHA 2013 heart failure guidelines recommend the use of ACE inhibitors, along with other guideline directed medical therapies, to prevent HF in patients with a reduced ejection fraction who have a history of MI (stage B HF), to prevent HF in any patient with a reduced ejection fraction (stage B HF), or to treat those with HF and reduced ejection fraction (stage C HFrEF) (Yancy, 2013).

Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients:

• Patients ≥60 years of age with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

• Patients <60 years of age with SBP ≥140 mm Hg or DBP is ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with diabetes and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with chronic kidney disease (CKD) and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.

Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with CAD recommends the use of an ACE inhibitor (or an ARB) as part of a regimen in patients with hypertension and chronic stable angina if there is prior MI, LV systolic dysfunction, diabetes mellitus, or CKD. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).

STEMI: The 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of patients with ST-elevation myocardial infarction (STEMI) states that an ACE inhibitor should be initiated within the first 24 hours after STEMI in patients with anterior MI, heart failure, or left ventricular ejection fraction (LVEF) of 0.4 or less. It is also reasonable to initiate an ACE inhibitor in all patients with STEMI (O'Gara, 2013).

Contraindications

Hypersensitivity to lisinopril, other ACE inhibitors, or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; idiopathic or hereditary angioedema; concomitant use with aliskiren in patients with diabetes mellitus

Documentation of allergenic cross-reactivity for ACE inhibitors is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Concomitant use with aliskiren-containing drugs in patients with moderate-to-severe renal impairment (GFR <60 mL/minute/1.73 m2)

Dosage

Acute myocardial infarction (within 24 hours in hemodynamically stable patients): Adults: Oral: 5 mg immediately, then 5 mg at 24 hours, 10 mg at 48 hours, and 10 mg every day thereafter for 6 weeks. Patients should continue to receive standard treatments such as thrombolytics, aspirin, and beta-blockers.

According to the 2013 ACCF/AHA guidelines for STEMI: Initial: 2.5 to 5 mg once daily; titrate to 10 mg daily or higher as tolerated (O'Gara, 2013).

Note: For patients with SBP 100 to 120 mm Hg following infarct, initiate therapy with 2.5 mg once daily for 3 days; if SBP falls to <100 mm Hg give maintenance dose of 5 mg once daily (may temporarily reduce to 2.5 mg once daily if necessary). Discontinue if SBP <90 mm Hg for > 1 hour.

Heart failure: Adults: Oral: Initial

US labeling: 2.5 to 5 mg once daily; then increase by no more than 10 mg increments at intervals no less than 2 weeks to a maximum dose of 40 mg daily. Usual maintenance: 5 to 40 mg daily as a single dose. Target dose: 20 to 40 mg once daily (ACCF/AHA [Yancy, 2013])

Note: If patient has hyponatremia (serum sodium <130 mEq/L) or renal impairment (CrCl <30 mL/minute or creatinine >3 mg/dL), then initial dose should be 2.5 mg once daily

Canadian labeling: 2.5 mg once daily; then increase by no more than 10 mg increments at intervals no less than 2 weeks to a maximum dose of 35 mg daily.

Hypertension:

Children ≥6 years and Adolescents: Oral:

US labeling: Initial: 0.07 mg/kg once daily (up to 5 mg); increase dose at 1- to 2-week intervals up to a maximum dose of 0.61 mg/kg or 40 mg once daily; doses >0.61 mg/kg or >40 mg have not been evaluated.

Canadian labeling:

20 kg to <50 kg: Initial: 2.5 mg once daily; titrate per response up to a maximum dose of 20 mg daily

≥50 kg: Initial: 5 mg once daily; titrate per response up to a maximum dose of 40 mg daily

Adults: Oral: Initial: 10 mg once daily (not maintained on a diuretic) or 5 mg once daily (maintained on a diuretic). Target dose (JNC 8 [James, 2013]): 40 mg once daily; usual dosage range (ASH/ISH [Weber, 2014]): 10 to 40 mg daily

Note: Antihypertensive effect may diminish toward the end of the dosing interval especially with doses of 10 mg daily. An increased dose may aid in extending the duration of antihypertensive effect. Doses up to 80 mg daily have been used, but do not appear to give greater effect.

Patients taking diuretics should have them discontinued 2 to 3 days prior to initiating lisinopril if possible. Restart diuretic after blood pressure is stable if needed.

Patients with renovascular hypertension (particularly those with unilateral/bilateral renal artery stenosis): Canadian labeling: Initial: 2.5 to 5 mg once daily with close monitoring; titrate dose carefully based on response.

Elderly: Consider lower initial doses (eg, 2.5 to 5 mg once daily) and titrate to response (Aronow, 2011)

Dosage adjustment in renal impairment:

Acute myocardial infarction (within 24 hours in hemodynamically stable patients): Adults:

US labeling:

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl 10 to 30 mL/minute: Initial: 2.5 mg once daily

CrCl <10 mL/minute: Initial: 2.5 mg once daily

Hemodialysis: Initial: 2.5 mg once daily (dialyzable)

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; not recommended if serum creatinine >177 micromol/L and/or proteinuria >500 mg/24 hour; consider discontinuing therapy if serum creatinine >265 micromol/L or doubles from baseline during therapy.

Heart failure: Adults: Initial doses should be modified and upward titration should be cautious, based on response (maximum: 40 mg daily)

US labeling:

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl 10 to 30 mL/minute or creatinine >3 mg/dL: Initial: 2.5 mg once daily

CrCl <10 mL/minute: Initial: 2.5 mg once daily

Hemodialysis: Initial: 2.5 mg once daily (dialyzable)

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling.

Hypertension:

Children ≥ 6 years and Adolescents:

GFR >30 mL/minute/1.73 m2: No dosage adjustment necessary.

GFR <30 mL/minute/1.73 m2: Use is not recommended.

Adults: Initial doses should be modified and upward titration should be cautious, based on response (maximum: 40 mg daily)

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl 10 to 30 mL/minute: Initial: 5 mg once daily (US labeling) or 2.5 to 5 mg once daily (Canadian labeling)

CrCl <10 mL/minute: Initial: 2.5 mg once daily

Hemodialysis: Initial: 2.5 mg once daily (dialyzable)

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Extemporaneously Prepared

A 1 mg/mL lisinopril oral suspension may be made with tablets and a mixture of Bicitra and Ora-Sweet SF. Place ten 20 mg tablets into an 8 ounce amber polyethylene terephthalate (PET) bottle and then add 10 mL purified water and shake for at least 1 minute. Gradually add 30 mL of Bicitra and 160 mL of Ora-Sweet SF to the bottle and gently shake after each addition to disperse the contents. Store resulting suspension at ≤25°C (77°F) for up to 4 weeks. Label bottle “shake well” (Prinivil prescribing information, 2013; Thompson, 2003).

A 1 mg/mL lisinopril oral suspension may be made with tablets and a 1:1 mixture of Ora-Plus® and Ora-Sweet®. Crush ten 10 mg tablets in a mortar and reduce to a fine powder. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 100 mL; transfer to a graduated cylinder; rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Store in amber plastic prescription bottles; label "shake well". Stable for 13 weeks at room temperature or refrigerated (Nahata, 2004).

A 1 mg/mL lisinopril oral suspension also be made with tablets, methylcellulose 1% with parabens, and simple syrup NF. Crush ten 10 mg tablets in a mortar and reduce to a fine powder. Add 7.7 mL of methylcellulose gel and mix to a uniform paste; mix while adding the simple syrup in incremental proportions to almost 100 mL; transfer to a graduated cylinder; rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Store in amber plastic prescription bottles; label "shake well". Stable for 13 weeks refrigerated or 8 weeks at room temperature (Nahata, 2004).

A 2 mg/mL lisinopril syrup may be made with powder (Sigma Chemical Company, St. Louis, MO) and simple syrup. Dissolve 1 g of lisinopril powder in 30 mL of distilled water. Mix while adding simple syrup in incremental proportions in a quantity sufficient to make 500 mL. Label "shake well" and "refrigerate". Stable for 30 days when stored in amber plastic prescription bottles at room temperature or refrigerated. Note: Although no visual evidence of microbial growth was observed, the authors recommend refrigeration to inhibit microbial growth (Webster, 1997).

Nahata MC and Morosco RS, "Stability of Lisinopril in Two Liquid Dosage Forms," Ann Pharmacother, 2004, 38(3):396-9.14742834Prinivil (lisinopril) [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; February 2013.Thompson KC, Zhao Z, Mazakas JM, et al, "Characterization of an Extemporaneous Liquid Formulation of Lisinopril," Am J Health Syst Pharm, 2003, 60(1):69-74.12533979Webster AA, English BA, and Rose DJ, "The Stability of Lisinopril as an Extemporaneous Syrup," Intr J Pharmaceut Compound, 1997, 1:352-3.

Administration

Administer as a single daily dose and without regard to meals.

Dietary Considerations

Use potassium-containing salt substitutes cautiously in patients with diabetes, patients with renal dysfunction, or those maintained on potassium supplements or potassium-sparing diuretics.

Storage

Store at room temperature. Protect from moisture, freezing, and excessive heat.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of ACE Inhibitors. Aliskiren may enhance the hypotensive effect of ACE Inhibitors. Aliskiren may enhance the nephrotoxic effect of ACE Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of ACE Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

AzaTHIOprine: ACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

Ciprofloxacin (Systemic): ACE Inhibitors may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of ACE Inhibitors. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Drospirenone: ACE Inhibitors may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Monitor therapy

Gold Sodium Thiomalate: ACE Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Monitor therapy

Grass Pollen Allergen Extract (5 Grass Extract): ACE Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Consider therapy modification

Heparin: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Icatibant: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

Iron Dextran Complex: ACE Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Consider therapy modification

Lanthanum: May decrease the serum concentration of ACE Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Consider therapy modification

Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: ACE Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. 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. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Pregabalin: ACE Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sacubitril: ACE Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Avoid combination

Salicylates: May enhance the nephrotoxic effect of ACE Inhibitors. Salicylates may diminish the therapeutic effect of ACE Inhibitors. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

Sodium Phosphates: ACE Inhibitors 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 ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

Thiazide Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

TiZANidine: May enhance the hypotensive effect of Lisinopril. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

Note: Frequency not always defined. Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with heart failure. However, the frequency of adverse effects associated with placebo is also increased in this population.

>10%:

Cardiovascular: Hypotension (7% to 11%)

Central nervous system: Dizziness (12% to 19%)

Renal: Increased blood urea nitrogen (2% to ≤11%), increased serum creatinine (≤2% to ≤11%; often transient)

1% to 10%:

Cardiovascular: Syncope (5% to 7%), flushing (≥1%), orthostatic effect (≥1%), chest pain

Central nervous system: Altered sense of smell (≥1%), fatigue (≥1%), headache

Dermatologic: Alopecia (≥1%), diaphoresis (≥1%), erythema (≥1%), pruritus (≥1%), skin photosensitivity (≥1%), Stevens-Johnson syndrome (≥1%), toxic epidermal necrolysis (≥1%), urticaria (≥1%)

Endocrine & metabolic: Increased nonprotein nitrogen (7%), hyperkalemia (2% to 6%), diabetes mellitus (≥1%), gout (≥1%), SIADH (≥1%)

Gastrointestinal: Constipation (≥1%), diarrhea (≥1%), dysgeusia (≥1%), flatulence (≥1%), pancreatitis (≥1%), xerostomia (≥1%)

Genitourinary: Impotence (≥1%)

Hematologic & oncologic: Bone marrow depression (≥1%), hemolytic anemia (≥1%), leukopenia (≥1%), neutropenia (≥1%), thrombocytopenia (≥1%), decreased hematocrit (small), decreased hemoglobin (small)

Infection: Common cold (1%)

Neuromuscular & skeletal: Weakness (≥1%)

Ophthalmic: Blurred vision (≥1%), diplopia (≥1%), photophobia (≥1%), vision loss (≥1%)

Otic: Tinnitus (≥1%)

Renal: Renal insufficiency (in patients with acute myocardial infarction: 2%)

Respiratory: Cough

<1% (Limited to important or life-threatening): Acute renal failure, anaphylactoid reactions, angioedema, anuria, arthralgia, arthritis, asthma, ataxia, azotemia, bronchitis, bronchospasm, cardiac arrest, cardiac arrhythmia, cerebrovascular acciden (possibly secondary to excessive hypotension in high risk patients), chills, confusion, cutaneous pseudolymphoma, dehydration, drowsiness, dyspepsia, dyspnea, dysuria, eosinophilia, eosinophilic pneumonitis, epistaxis, facial edema, fever, gastritis, hallucination, heartburn, hemoptysis, hepatic necrosis, hepatitis (hepatocellular jaundice or cholestatic jaundice), herpes zoster, hypersomnia, hypervolemia, hypoglycemia (diabetic patients on oral antidiabetic agents or insulin), hyponatremia, increased erythrocyte sedimentation rate, insomnia, intestinal angioedema, irritability, laryngitis, leukocytosis, malaise, malignant neoplasm of lung, mastalgia, memory impairment, mood changes (including depressive symptoms), muscle spasm, musculoskeletal pain, myalgia, myocardial infarction (possibly secondary to excessive hypotension in high risk patients), oliguria, orthopnea, orthostatic hypotension, palpitations, paresthesia, paroxysmal nocturnal dyspnea, pemphigus, peripheral edema, peripheral neuropathy, pharyngitis, pleural effusion, pneumonia, positive ANA titer, psoriasis, pulmonary embolism, pulmonary infarct, pulmonary infiltrates, pyelonephritis, rhinitis, rhinorrhea, sinusitis, skin infection, skin lesion, skin rash, sore throat, systemic lupus erythematosus, transient ischemic attacks, tremor, uremia, urinary tract infection, vasculitis, vertigo, viral infection, visual hallucination (Doane, 2013), weight gain, weight loss, wheezing

ALERT: U.S. Boxed Warning

Fetal toxicity:

When pregnancy is detected, discontinue lisinopril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: At any time during treatment (especially following first dose), angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). African-Americans may be at an increased risk. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) therapy. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE inhibitor therapy is contraindicated.

• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice or hepatitis, which may progress to fulminant hepatic necrosis (sometimes fatal); discontinue if marked elevation of hepatic transaminases or jaundice occurs. Use with caution in patients with preexisting hepatic impairment; consider baseline hepatic function tests prior to initiating therapy.

• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1-4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.

• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.

• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur with ACE inhibitors (usually with the first several doses). Effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation. Other patients at risk include those with heart failure and systolic blood pressure <100 mm Hg, ischemic heart disease, cerebrovascular disease, renal dialysis, hyponatremia, high-dose diuretic therapy, severe aortic stenosis, or hypertrophic cardiomyopathy. Close monitoring of patients is required especially within the first few weeks of initial dosing and with dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation. Avoid use in hemodynamically unstable patients after acute MI.

• Neutropenia/agranulocytosis: Another ACE Inhibitor, captopril, has been associated with rare cases of agranulocytosis, neutropenia, or leukopenia with myeloid hypoplasia. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Periodically monitor CBC with differential in these patients.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.

• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution in pre-existing renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment. In acute myocardial infarction, the Canadian labeling does not recommend initiating therapy if serum creatinine >177 micromol/L and/or proteinuria >500 mg/24 hour and recommends considering discontinuing therapy if serum creatinine >265 micromol/L or doubles from baseline during therapy. In a retrospective cohort study of elderly patients (≥65 years) with myocardial infarction and impaired left ventricular function, administration of an ACE inhibitor was associated with a survival benefit, including patients with serum creatinine concentrations >3 mg/dL (265 micromol/L) (Frances, 2000).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

Other warnings/precautions:

• Surgery: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis, 2011).

Monitoring Parameters

BUN, serum creatinine, renal function, WBC, and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential; hypotensive effects within 1 to 3 hours of initial dose or with increased dosages; consider baseline hepatic function tests (if preexisting hepatic impairment)

2013 ACCF/AHA Heart Failure guideline recommendations: Within 1-2 weeks after initiation and periodically thereafter, reassess renal function and serum potassium especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or those taking potassium supplements (ACCF/AHA [Yancy, 2013]).

Pregnancy Risk Factor

D

Pregnancy Considerations

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Lisinopril crosses the placenta.

Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. The use of these drugs in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Teratogenic effects may occur following maternal use of an ACE inhibitor during the first trimester, although this finding may be confounded by maternal disease. Because adverse fetal events are well documented with exposure later in pregnancy, ACE inhibitor use in pregnant women is not recommended (Seely 2014; Weber 2014). Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.

Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant and mother. ACE inhibitors are not recommended for the treatment of uncomplicated hypertension in pregnancy (ACOG 2013) and they are specifically contraindicated for the treatment of hypertension and chronic heart failure during pregnancy by some guidelines (Regitz-Zagrosek 2011). In addition, ACE inhibitors should generally be avoided in women of reproductive age (ACOG 2013). If treatment for hypertension or chronic heart failure in pregnancy is needed, other agents should be used (ACOG 2013; Regitz-Zagrosek 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache. Have patient report immediately to prescriber signs of renal impairment, signs of hyperkalemia, signs of infection, severe dizziness, syncope, considerable dyspepsia, significant nausea, angina, or signs of hepatic impairment (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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