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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: Management of hypertension in adult and pediatric patients 6 years and older (monotherapy or in combination with other antihypertensives).
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 (OGara, 2013).
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).
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.
Acute myocardial infarction (within 24 hours in hemodynamically stable patients): Oral: 5 mg immediately, then 5 mg at 24 hours, 10 mg at 48 hours, and then 10 mg once daily 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 (OGara, 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:
US labeling: Initial: 2.5 to 5 mg once daily; increase by no more than 10 mg increments at intervals no less than 2 weeks to the highest tolerated dose (maximum: 40 mg/day). Usual maintenance: 5 to 40 mg once daily. Target dose: 20 to 40 mg once daily (ACCF/AHA [Yancy 2013])
Note: If patient has hyponatremia (serum sodium <130 mEq/L), 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, maximum: 35 mg/day
Hypertension: Oral: Initial: 10 mg once daily (not maintained on a diuretic) or 5 mg once daily (maintained on a diuretic); adjust dose according to blood pressure response. 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. If possible, discontinue diuretics 2 to 3 days prior to initiating lisinopril; restart diuretic, if needed, after blood pressure is stable.
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.
Refer to adult dosing. In the management of hypertension, consider lower initial doses (eg, 2.5 to 5 mg once daily) and titrate to response (Aronow, 2011).
Hypertension:
US labeling:
Children <6 years (off-label population): Limited data available: Oral: Initial: 0.07 to 0.1 mg/kg once daily (maximum initial dose: 5 mg/day); increase dose at 1- to 2-week intervals; maximum: 0.6 mg/kg/day or 40 mg/day (NHBPEP 2004, NHLBI 2011, Raes 2007).
Children ≥6 years and Adolescents: Oral: Initial: 0.07 to 0.1 mg/kg once daily (maximum initial dose: 5 mg/day); increase dose at 1- to 2-week intervals; maximum: 0.6 mg/kg/day or 40 mg/day (NHBPEP 2004, NHLBI 2011, Raes 2007).
Canadian labeling: Children ≥6 years and Adolescents: Oral:
20 kg to <50 kg: Initial: 2.5 mg once daily; adjust dose according to blood pressure response; maximum: 20 mg/day.
≥50 kg: Initial: 5 mg once daily; adjust dose according to blood pressure response; maximum: 40 mg/day.
Adults:
Acute myocardial infarction (within 24 hours in hemodynamically stable patients):
US labeling:
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 30 mL/minute: Initial: 2.5 mg once daily (maximum: 40 mg/day).
CrCl <10 mL/minute: Initial: 2.5 mg once daily (maximum: 40 mg/day).
Hemodialysis: Initial: 2.5 mg once daily (dialyzable) (maximum: 40 mg/day).
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:
CrCl >30 mL/minute: No dosage adjustment necessary.
CrCl 10 to 30 mL/minute: Initial: 2.5 mg once daily (maximum: 40 mg/day)
CrCl <10 mL/minute: Initial: 2.5 mg once daily (maximum: 40 mg/day)
Hemodialysis: Initial: 2.5 mg once daily (dialyzable) (maximum: 40 mg/day)
Hypertension:
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) (maximum: 40 mg/day)
CrCl <10 mL/minute: Initial: 2.5 mg once daily (maximum: 40 mg/day)
Hemodialysis: Initial: 2.5 mg once daily (dialyzable) (maximum: 40 mg/day)
In addition, the following dosage adjustments have been recommended (Aronoff 2007):
GFR >50 mL/minute: No dosage adjustment necessary.
GFR 10 to 50 mL/minute: Administer 50% to 75% of usual dose.
GFR <10 mL/minute: Administer 25% to 50% of usual dose.
Intermittent hemodialysis: Dose after dialysis.
Continuous renal replacement therapy (CRRT): Administer 50% to 75% of usual dose.
Children ≥ 6 years and Adolescents:
Manufacturers labeling:
GFR >30 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR <30 mL/minute/1.73 m2: Use is not recommended.
In addition, the following dosage adjustments have been recommended (Aronoff 2007):
GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary.
GFR 10 to 50 mL/minute/1.73 m2: Administer 50% of usual dose.
GFR <10 mL/minute/1.73 m2: Administer 25% of usual dose.
Intermittent hemodialysis: Administer 25% of usual dose.
Peritoneal dialysis (PD): Administer 25% of usual dose.
Continuous renal replacement therapy (CRRT): Administer 50% of usual dose.
There are no dosage adjustments provided in the manufacturer 's labeling; use with caution.
Administer as a single daily dose and without regard to meals.
Use potassium-containing salt substitutes cautiously in patients with diabetes, patients with renal impairment, or those maintained on potassium supplements or potassium-sparing diuretics.
Store at 20 � �C to 25 � �C (68 � �F to 77 � �F). Protect from moisture, freezing, and excessive heat.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Qbrelis: 1 mg/mL (150 mL) [contains sodium benzoate]
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
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.[PMID: 14742834]Prinivil (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.[PMID: 12533979]Webster AA, English BA, and Rose DJ, "The Stability of Lisinopril as an Extemporaneous Syrup," Intr J Pharmaceut Compound, 1997, 1:352-3.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
Ferric Hydroxide Polymaltose Complex: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. 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
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicergoline: 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
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. 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
Quinagolide: 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 and Thiazide-Like Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Thiazide and Thiazide-Like 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
Blood pressure, heart rate; BUN, serum creatinine, and potassium; consider baseline LFTs (if preexisting hepatic impairment); monitor for jaundice or signs of hepatic failure; In patients with collagen vascular disease and/or renal impairment, periodically monitor CBC with differential.
2013 ACCF/AHA Heart Failure guideline recommendations: Within 1 to 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]).
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
Decreased elimination when glomerular filtration rate is ≤30 mL/minute. With greater impairment, peak and trough lisinopril levels increase, time to peak concentration increases, and time to attain steady state is prolonged.
Heart Failure (New York Heart Association class II through IV): Vd is slightly smaller.
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 (some fatal); discontinue if marked elevation of hepatic transaminases or jaundice occurs.
- 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 to 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.
- Hematologic effects: Another ACE Inhibitor, captopril, has been associated with neutropenia with myeloid hypoplasia and agranulocytosis; anemia and thrombocytopenia have also occurred. 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.
- Hyperkalemia: May occur with ACE inhibitors; risk factors include renal impairment, 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. 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 patients 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. In acute MI, the Canadian labeling does not recommend use if systolic blood pressure is <100 mm Hg.
- Renal function deterioration: May be associated with deterioration of renal function and/or increases in BUN and 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 benign increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function (Bakris 2000).
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.
- Hepatic impairment: Use with caution in patients with hepatic impairment; consider baseline LFTs prior to initiating therapy.
- 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 (ACCF/AHA [Gersh, 2011]).
- 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. In acute MI, the Canadian labeling does not recommend initiating therapy in patients with a history of bilateral renal artery stenosis.
- Renal impairment: Use with caution in preexisting renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment. In acute MI, the Canadian labeling does not recommend initiating therapy if clinically relevant renal failure is present, if serum creatinine >177 micromol/L and/or proteinuria >500 mg per 24 hours 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 MI 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.
Dosage form specific issues:
- Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol ( ≥99 mg/kg/day) have been associated with a potentially fatal toxicity (gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982). Some data suggest that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
Special populations:
- Black patients: ACE inhibitors effectiveness is less in black patients than in non-black patients. In addition, ACE inhibitors cause a higher rate of angioedema in black than in non-black patients.
- 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).
[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).
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
Not metabolized
Primarily urine (as unchanged drug)
1 hour; Peak effect: Hypotensive: Oral: ~6 hours
Pediatric patients 6 months to 15 years: Median (range): 5 to 6 hours (Hogg 2007)
Adults: ~7 hours
24 hours
12 hours
- 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 kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling), signs of infection, severe dizziness, passing out, persistent cough, severe abdominal pain, severe nausea, vomiting, or angina (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.