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Lisinopril

Medically reviewed on August 12, 2018

Pronunciation

(lyse IN oh pril)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

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, 5 mg [DSC]

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
  • Qbrelis
  • 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

Metabolism

Not metabolized

Excretion

Primarily urine (as unchanged drug)

Onset of Action

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

Time to Peak

Pediatric patients 6 months to 15 years: Median (range): 5 to 6 hours (Hogg 2007)

Adults: ~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/minute. With greater impairment, peak and trough lisinopril levels increase, time to peak concentration increases, and time to attain steady state is prolonged.

Special Populations Note

Heart Failure (New York Heart Association class II through IV): 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

Guideline recommendations: Based on the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of patients with ST-elevation acute coronary syndromes (STE-ACS), an ACE inhibitor should be initiated within the first 24 hours to all patients with STE-ACS with anterior location, heart failure (HF), or left ventricular ejection fraction (LVEF) ≤40%, unless contraindicated. It is also reasonable to initiate an ACE inhibitor in all patients with STE-ACS.

Heart failure: Adjunctive therapy to reduce signs and symptoms of systolic of HF

Guideline recommendations: The ACC/AHA 2013 Heart Failure Guidelines recommend the use of ACE inhibitors, along with other guideline-directed medical therapies, to prevent progression of HF and reduced ejection fraction in asymptomatic patients with or without a history of myocardial infarction (Stage B HF), or to treat those with symptomatic HF and reduced ejection fraction to reduce morbidity and mortality (Stage C HFrEF).

Hypertension: Management of hypertension in adult and pediatric patients ≥6 years of age

Guideline recommendations: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults recommends if monotherapy is warranted, in the absence of comorbidities (eg, cerebrovascular disease, chronic kidney disease, diabetes, HF, ischemic heart disease, etc.), that thiazide-like diuretics or dihydropyridine calcium channel blockers may be preferred options due to improved cardiovascular endpoints (eg, prevention of HF and stroke). ACE inhibitors and ARBs are also acceptable for monotherapy. Combination therapy may be required to achieve blood pressure goals and is initially preferred in patients at high risk (stage 2 hypertension or atherosclerotic cardiovascular disease [ASCVD] risk ≥10%) (ACC/AHA [Whelton 2017]).

Off Label Uses

Non–ST-elevation acute coronary syndrome

Based on the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), an ACE inhibitor should be initiated and continued indefinitely after NSTE-ACS in patients with a left ventricular ejection fraction (LVEF) ≤40% and in those with hypertension, diabetes mellitus, or stable CKD unless contraindicated. Use of an ACE inhibitor may also be useful in all other patients with cardiac or other vascular disease.

Stable coronary artery disease

Based on the ACC/AHA guideline for the diagnosis and management of patients with stable ischemic heart disease, an ACE inhibitor or ARB should be prescribed in all patients with stable ischemic heart disease who also have hypertension, diabetes mellitus, LVEF <40%, or CKD unless contraindicated.

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; coadministration with or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril).

Canadian labeling: Additional contraindications (not in US labeling): Women who are pregnant, intend to become pregnant, or of childbearing potential and not using adequate contraception; breastfeeding; concomitant use with aliskiren, angiotensin receptor blockers (ARBs), or other ACE inhibitors in patients with moderate to severe renal impairment (GFR <60 mL/minute/1.73 m2), hyperkalemia (>5 mMol/L), or with heart failure who are hypotensive; concomitant use with ARBs or other ACE inhibitors in diabetic patients with end organ damage; pediatric patients <6 years; pediatric patients 6 to 16 years of age with severe renal impairment (GFR <60 mL/minute/1.73 m2).

Dosing: Adult

Acute myocardial infarction (within 24 hours in hemodynamically stable patients): Oral: Initial: 2.5 to 5 mg once daily; titrate to 10 mg daily or higher as tolerated (ACC/AHA [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: Oral: 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); Target dose: 20 to 40 mg once daily (ACC/AHA [Yancy 2013])

Hypertension: Oral: Initial: 5 to 10 mg once daily; titrate dose as needed based on patient response up to 40 mg once daily (ACC/AHA [Whelton 2017])

Note: Doses up to 80 mg daily have been used, but do not appear to give greater effect.

Dosing: Geriatric

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).

Dosing: Pediatric

Hypertension: Note: Compounded and commercially available oral solutions available in multiple concentrations; precautions should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as mg.

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).

Dosing: Renal Impairment

Adults:

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

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).

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 (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:

Manufacturer's 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.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Extemporaneously Prepared

Note: A lisinopril oral solution (1 mg/mL) is commercially available (Qbrelis).

1 mg/mL Oral Suspension

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).

Nahata MC and Morosco RS. Stability of lisinopril in two liquid dosage forms. Ann Pharmacother. 2004;38(3):396-399.14742834

A 1 mg/mL lisinopril oral suspension may be made with tablets and a mixture of sodium citrate/citric acid oral solution or Cytra-2 diluent 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 sodium citrate/citric acid oral solution or Cytra-2 diluent 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 2016; Thompson 2003).

Prinivil (lisinopril) [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; October 2016.Thompson KC, Zhao Z, Mazakas JM, et al. Characterization of an extemporaneous liquid formulation of lisinopril. Am J Health Syst Pharm. 2003;60(1):69-74.12533979

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).

Nahata MC and Morosco RS. Stability of lisinopril in two liquid dosage forms. Ann Pharmacother. 2004;38(3):396-399.14742834

2 mg/mL Syrup

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).

Webster AA, English BA, and Rose DJ. The stability of lisinopril as an extemporaneous syrup. Intr J Pharmaceut Compound. 1997;1:352-353.

Administration

Oral: 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 impairment, or those maintained on potassium supplements or potassium-sparing diuretics.

Storage

Store at 15°C to 30°C (59°F to 86°F). Protect from moisture.

Drug Interactions

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

Aliskiren: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme 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: Angiotensin-Converting Enzyme 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: Angiotensin-Converting Enzyme Inhibitors may enhance the therapeutic effect of Angiotensin II. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

AzaTHIOprine: Angiotensin-Converting Enzyme Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

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

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

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

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

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Canagliflozin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Canagliflozin may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

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

Dipeptidyl Peptidase-IV Inhibitors: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Drospirenone: Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

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

Ferric Gluconate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Monitor therapy

Ferric Hydroxide Polymaltose Complex: Angiotensin-Converting Enzyme 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

Gelatin (Succinylated): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gelatin (Succinylated). Specifically, the risk of a paradoxical hypotensive reaction may be increased. Monitor therapy

Gold Sodium Thiomalate: Angiotensin-Converting Enzyme 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): Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Iron Dextran Complex: Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme 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: Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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 Angiotensin-Converting Enzyme 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: Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme 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

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. 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 Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Pregabalin: Angiotensin-Converting Enzyme 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: Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Sodium Phosphates: Angiotensin-Converting Enzyme 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 Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

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

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

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

Test Interactions

May lead to false-negative aldosterone/renin ratio (ARR) (Funder 2016)

Adverse Reactions

>10%:

Cardiovascular: Hypotension (4% to 11%)

Central nervous system: Dizziness (4% to 19%)

Renal: Increased serum creatinine (≤10%; transient), increased blood urea nitrogen (≤2%; transient)

1% to 10%:

Cardiovascular: Syncope (5% to 7%), chest pain (2% to 3%), flushing (≥1%), orthostatic effect (≥1%), vasculitis (≥1%)

Central nervous system: Headache (4% to 6%), altered sense of smell (≥1%), fatigue (≥1%), paresthesia (≥1%), vertigo (≥1%)

Dermatologic: Skin rash (≥1% to 2%), alopecia (≥1%), diaphoresis (≥1%), erythema (≥1%), pruritus (≥1%), skin photosensitivity (≥1%), Stevens-Johnson syndrome (≥1%), toxic epidermal necrolysis (≥1%), urticaria (≥1%)

Endocrine & metabolic: Hyperkalemia (2% to 6%), diabetes mellitus (≥1%), gout (≥1%), SIADH (≥1%)

Gastrointestinal: Diarrhea (≥1% to 4%), constipation (≥1%), dysgeusia (≥1%), flatulence (≥1%), pancreatitis (≥1%), xerostomia (≥1%)

Genitourinary: Impotence (≥1%)

Hematologic & oncologic: Bone marrow depression (≥1%), eosinophilia (≥1%), hemolytic anemia (≥1%), increased erythrocyte sedimentation rate (≥1%), leukocytosis (≥1%), leukopenia (≥1%), neutropenia (≥1%), positive ANA titer (≥1%), thrombocytopenia (≥1%; mean decrease of 0.4 mg/dL)

Neuromuscular & skeletal: Arthralgia (≥1%), arthritis (≥1%), myalgia (≥1%), 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: 1% to 2%)

Respiratory: Cough (3% to 4%)

Frequency not defined:

Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin (mean decrease of 1.3%)

Hepatic: Increased liver enzymes, increased serum bilirubin

<1%, postmarketing, and/or case reports: Acute renal failure, angioedema, confusion, cutaneous pseudolymphoma, dehydration, fever, hallucination, hypoglycemia (diabetic patients on oral antidiabetic agents or insulin), hyponatremia, mood changes (including depressive symptoms), psoriasis, visual hallucination

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 or a neprilysin inhibitor (eg, sacubitril). 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 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.

• 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.

• Ascites: Avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor blood pressure and renal function carefully to avoid rapid development of renal failure (AASLD [Runyon 2012]).

• 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.

• 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 a retrospective cohort study of elderly patients (≥65 years of age) 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.

• Surgical patients: 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). Based on current research and clinical guidelines in patients undergoing noncardiac surgery, continuing ACE inhibitors is reasonable in the perioperative period. If ACE inhibitors are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible (ACC/AHA [Fleisher 2014]).

Monitoring Parameters

Blood pressure, heart rate; BUN, serum creatinine, and potassium; consider baseline LFTs (if preexisting hepatic impairment); monitor for jaundice or signs of hepatic failure; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential.

Heart failure: 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]).

Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2017]):

Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%: Target blood pressure <130/80 mm Hg is recommended

Confirmed hypertension without markers of increased ASCVD risk: Target blood pressure <130/80 mm Hg may be reasonable

Diabetes and hypertension: The American Diabetes Association (ADA) guidelines (ADA 2017a; ADA 2017b):

Patients ≥18 to ≤65 years of age: Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg

Patients ≥18 to ≤65 years of age and at high risk of cardiovascular disease: Goal of therapy is SBP <130 mm Hg and DBP <80 mm Hg (if can be achieved without undue treatment burden)

Patients ≥65 years of age (healthy or complex/intermediate health): Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg

Patients ≥65 years of age (very complex/poor health): Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg

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 (Bhatt-Mehta 1993; Filler 2003).

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 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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