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Ramipril (Monograph)

Brand name: Altace
Drug class: Angiotensin-Converting Enzyme Inhibitors
- ACE Inhibitors
VA class: CV800
Chemical name: [2S-[1[R*(R*)],2α,3aβ,6aβ]]-1-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropy l]octahydrocylopenta[b]pyrrole-2-carboxylic acid
Molecular formula: C21H28N2O5
CAS number: 87333-19-5

Medically reviewed by Drugs.com on Oct 26, 2023. Written by ASHP.

Warning

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 39 40 41 42 43 44 45 46 88 89 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue ramipril as soon as possible.1 89

Introduction

Nonsulfhydryl ACE inhibitor.1 2 3

Uses for Ramipril

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 4 1200

ACE inhibitors are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics.501 502 503 504 1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 504 1200 1213

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).501 502 503 504 515 1200 1201

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.1200 However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.501 503 504 505 506 507 508 515 523 526 530 1200 1201 1207 1209 1222 1223 1229

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.1200 These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.1200 1202 1210

Other hypertension guidelines generally have based target BP goals on age and comorbidities.501 504 536 Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients501 504 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the current ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.1222 1223 1224 1229

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient’s BP treatment goal.1200 1220

For decisions regarding when to initiate drug therapy (BP threshold), the current ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.1200 1207 ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.1200

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).1200

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.1200

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.1200 Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.502 1200

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.1200 Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in patients with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.1200

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to ACE inhibitors.14 67 68 86 87 501 504 1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.1200

ACE inhibitors may be preferred in hypertensive patients with heart failure, ischemic heart disease, diabetes mellitus, CKD, or cerebrovascular disease or post-MI.501 502 504 523 524 525 526 527 534 535 536 543 1200 1214 1215

Heart Failure After Acute MI

Reduction of the risk of mortality in hemodynamically stable patients who have demonstrated clinical signs of heart failure within a few days following acute MI.1 2 12 18 21 24 27 28 524 Also may reduce rate of heart failure-associated hospitalization and progression to severe and/or resistant heart failure.1 2 12 18 21 24 27 28 524

Expert guidelines recommend initiation of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarct, heart failure, or ejection fraction ≤40% who do not have any contraindications (e.g., hypotension, shock, renal dysfunction).527 Use with caution (and with gradual upward titration) during initial postinfarction period because of the possibility of hypotension or renal dysfunction.527 1100

Continue therapy indefinitely in patients with left ventricular dysfunction or other compelling indications (e.g., hypertension, diabetes mellitus, CKD).525 1100

Prevention of Major Cardiovascular Events

Reduction of the risk of cardiovascular death, MI, and stroke in patients ≥55 years of age who are at high risk for cardiovascular events (e.g., those with a history of CAD, stroke, peripheral vascular disease, or diabetes mellitus in addition to ≥1 other cardiovascular risk factor [e.g., hypertension, elevated total cholesterol and/or decreased HDL-cholesterol concentrations, smoking, documented microalbuminuria]) but who are not known to have low ventricular ejection fraction or heart failure.1 47 48

Reduction in the incidence of diabetic complications and in new diagnosis of diabetes also reported.47 48

Heart Failure

Management of heart failure [off-label], usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-adrenergic blocking agents (β-blockers).70 71 72 73 74 524 800

Some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.702 800

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.701 800

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria [off-label] who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.81 82 83 84 85 535 536 1232

Ramipril Dosage and Administration

General

BP Monitoring and Treatment Goals

Administration

Oral Administration

Administer orally once or twice daily.1

Swallow capsules whole.1 Alternatively, open capsules and sprinkle contents on small amount (about 120 mL) of applesauce or mix in 120 mL of water or apple juice.1 Consume entire mixture to ensure that no drug is lost.1 (See Storage under Stability.)

Dosage

In patients currently receiving diuretic therapy, discontinue diuretic, reduce diuretic dosage, or increase salt intake prior to initiating ramipril.600 If such changes are not possible, initiate ramipril in adults at a reduced dosage of 1.25 mg once daily.600 (See Hypotension under Cautions and see the individual dosage sections in Dosage and Administration.)

Adults

Hypertension
Oral

Initially, 2.5 mg once daily in patients not receiving diuretic therapy.600 In patients receiving a diuretic, initiate ramipril at 1.25 mg once daily.600 Adjust subsequent dosage based on BP response.600

Usual maintenance dosage: 2.5–20 mg daily, given in 1 dose or 2 divided doses.600 1200

If effectiveness diminishes toward end of dosing interval in patients treated once daily, consider increasing dosage or administering drug in 2 divided doses.600

Heart Failure After Acute MI
Oral

Initially, 2.5 mg twice daily.1 12 Some clinicians recommend initiation of therapy within the first 24 hours following MI.527 If hypotension occurs, reduce dosage to 1.25 mg twice daily.1 After 1 week at initial dosage, adjust dosage as tolerated at 3-week intervals to target dosage of 5 mg twice daily.1

Following initial dose, monitor closely for ≥2 hours and until BP has stabilized for at least an additional hour.1 To minimize risk of hypotension, reduce diuretic dosage, if possible.1

Prevention of Major Cardiovascular Events
Oral

Initially, 2.5 mg once daily for 1 week, followed by 5 mg once daily for 3 weeks; subsequently increase dosage as tolerated to maintenance dosage of 10 mg once daily.1 In patients with hypertension or those with recent MI, may administer total daily dosage in divided doses.1

Heart Failure† [off-label]
Oral

Initially, 1.25–2.5 mg once daily recommended by ACCF and AHA in patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure).524

Titrate dosage slowly upward as tolerated to dosages shown to reduce the risk of cardiovascular events in clinical trials; may use intermediate doses if such target dosages cannot be achieved or are poorly tolerated.524

ACCF and AHA recommend maximum ramipril dosage of 10 mg once daily for patients with ACCF/AHA stage C heart failure.524

Special Populations

Renal Impairment

Initial dosage of 1.25 mg once daily recommended in patients with renal artery stenosis.1

In patients with Clcr <40 mL/minute, 25% of the usual doses are expected to induce full therapeutic concentrations of ramiprilat.1

Hypertension
Oral

Initially, 1.25 mg once daily in patients with Clcr <40 mL/minute.1 Titrate until BP is controlled or to maximum dosage of 5 mg daily.1

Heart Failure After Acute MI
Oral

Initially, 1.25 mg once daily in patients with Clcr <40 mL/minute.1 May increase dosage to 1.25 mg twice daily; subsequently titrate according to clinical response and tolerance up to maximum dosage of 2.5 mg twice daily.1

Volume-and/or Salt-Depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy at dosage of 1.25 mg once daily.1

Cautions for Ramipril

Contraindications

Warnings/Precautions

Warnings

Hepatic Effects

Clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (occasionally fatal) reported rarely with ACE inhibitors.1

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.1

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those receiving prolonged diuretic therapy or undergoing dialysis, those with dietary salt restriction, patients with diarrhea or vomiting).1 Risk of excessive hypotension, sometimes associated with oliguria, azotemia, and, rarely, acute renal failure and death in patients with heart failure with or without associated renal insufficiency.1

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.1

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical circumstances.1 Correct volume and/or salt depletion (e.g., by withholding diuretic therapy, reducing diuretic dosage, increasing sodium intake) prior to initiation of ramipril or reduce initial dosage.1 600 (See Dosage and also Special Populations, under Dosage and Administration.)

In patients at risk of excessive hypotension, initiate therapy under close medical supervision; monitor closely for first 2 weeks following initiation of ramipril or any increase in ramipril or diuretic dosage.1

If hypotension occurs, place patient in supine position and, if necessary, administer IV infusion of physiological saline.1 Ramipril therapy usually can be continued following restoration of volume and BP.1

Hematologic Effects

Neutropenia and agranulocytosis reported with captopril; risk appears to depend principally on presence of renal impairment and/or presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma);1 also reported in patients receiving immunosuppressive therapy.5 6 Hematologic effects (e.g., agranulocytosis; pancytopenia; bone marrow depression; reductions in hemoglobin content or leukocyte, erythrocyte, or platelet counts) reported rarely with ramipril.1

Consider monitoring leukocytes in patients with collagen vascular disease, especially if renal impairment exists.1

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.1 88 89 (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.89

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.88 89

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.89 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.44 46

Sensitivity Reactions

Anaphylactoid reactions and/or head and neck angioedema possible; if associated with laryngeal edema, may be fatal.1 Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.1

Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.1

Increased risk for angioedema also reported with concomitant mammalian target of rapamycin (mTOR) inhibitor (e.g., temsirolimus) therapy.600

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption or following initiation of hemodialysis that utilized high-flux membrane.1

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.1

Contraindicated in patients with a history of angioedema associated with ACE inhibitors.1 47 Patients with history of angioedema unrelated to ACE inhibitors may be at increased risk of angioedema associated with ACE inhibitor therapy.1

General Precautions

Renal Effects

Transient increases in BUN and Scr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy.1 Possible increases in BUN and Scr in patients with unilateral or bilateral renal artery stenosis; generally reversible following discontinuance of ramipril and/or diuretic therapy.1

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe heart failure.1

Closely monitor renal function for the first few weeks of therapy in hypertensive patients with unilateral or bilateral renal-artery stenosis.1 Some patients may require dosage reduction or discontinuance of ACE inhibitor or diuretic therapy.1

Hyperkalemia

Possible hyperkalemia, especially in patients with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).1 (See Interactions.)

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.1

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and see Boxed Warning.)

Lactation

Undetectable in human milk following single oral dose; not known whether distributed into milk following multiple doses.1 Use not recommended.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Use with caution in patients with cirrhosis and/or ascites, due to possible increased activity of renin-angiotensin-aldosterone system.1

Possible marked increase in plasma ramipril concentrations; peak plasma ramiprilat concentrations not appreciably altered. (See Absorption: Special Populations, under Pharmacokinetics.)1

Renal Impairment

Systemic exposure to ramiprilat may be increased.1 (See Pharmacokinetics.) Initial dosage adjustment may be necessary depending on degree of renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Deterioration of renal function may occur.1 (See Renal Effects under Cautions.)

Black Patients

BP reduction may be smaller in black patients compared with nonblack patients.1 14 15 67 68 (See Hypertension under Uses.)

Higher incidence of angioedema reported with ACE inhibitors in black patients compared with other races.1 68 1200

Common Adverse Effects

Patients with hypertension: Headache, dizziness, fatigue.1

Patients with heart failure: Dizziness, cough, nausea, vomiting, angina pectoris, syncope, postural hypotension, vertigo, hypotension.1

Drug Interactions

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Increased risk of renal impairment, hyperkalemia, and hypotensiona

Generally avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantlya

Aliskiren

Increased risk of renal impairment, hyperkalemia, and hypotensiona 550

Generally avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantlya 550

Concomitant use contraindicated in patients with diabetes mellitusa 550

Avoid concomitant use in patients with GFR <60 mL/minutea 550

Angiotensin II receptor antagonists

Increased risk of renal impairment, hyperkalemia, and hypotensiona

Generally avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantlya

Antacid

Pharmacokinetic interaction unlikely1

Antidiabetic agents (insulin, oral agents)

Possible hypoglycemia in diabetic patients1

Monitor closely for symptoms of hypoglycemia following initiation or dosage adjustment of ramipril; adjust dosage of antidiabetic agent as necessary1

Cimetidine

Pharmacokinetic interaction unlikely1

Digoxin

Pharmacokinetic interaction unlikely1

Diuretics

Increased hypotensive effect1

If possible, discontinue or decrease dosage of diuretic before initiating ramipril600 (see Dosage and also Special Populations, under Dosage and Administration)

Diuretics, potassium-sparing (amiloride, spironolactone, triamterene)

Enhanced hyperkalemic effect1

Use with caution; monitor serum potassium concentrations frequently1

Lithium

Increased serum lithium concentrations; possible toxicity1

Use with caution; monitor serum lithium concentrations frequently1

Mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus)

Increased risk for angioedema600

NSAIAs

Potential for reduction of renal function and increase in serum potassium1

No interaction observed with indomethacin1

Potassium supplements or potassium-containing salt substitutes

Enhanced hyperkalemic effect1

Use with caution; monitor serum potassium concentrations frequently1

Simvastatin

Pharmacokinetic interaction unlikely1

Warfarin

Pharmacologic interaction unlikely1

Ramipril Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations of ramipril usually attained within 1 hour.1 Peak plasma concentrations of ramiprilat attained within 2–4 hours after oral dose.1 About ≥50–60% of an oral dose is absorbed.1

Onset

Following multiple oral doses (≥2 mg), >90% inhibition of plasma ACE activity achieved 4 hours after dosing.1

Duration

Following multiple oral doses (≥2 mg), inhibition of >80% of plasma ACE activity persists for about 24 hours.1

Food

Food decreases rate but not extent of absorption.1 Opening the capsules and sprinkling the contents on applesauce or mixing the contents in apple juice does not alter serum concentrations of ramiprilat.1 (See Oral Administration under Dosage and Administration.)

Special Populations

In patients with hepatic impairment, plasma concentrations of ramipril are increased; peak plasma ramiprilat concentrations are similar to those in individuals with normal hepatic function.1

In patients with renal impairment (Clcr <40 mL/minute per 1.73 m2), plasma concentrations and AUC of ramiprilat are increased, and time to peak plasma ramiprilat concentrations is slightly prolonged.1

Distribution

Extent

Distributes into a large peripheral compartment.1 Crosses the placenta.1 Undetectable in human milk following single oral dose; not known whether distributed into milk following multiple doses.1

Plasma Protein Binding

Ramipril: About 73%.1

Ramiprilat: About 56%.1

Elimination

Metabolism

Metabolized mainly in the liver, principally to an active metabolite, ramiprilat.1

Elimination Route

Excreted in urine (60%) as unchanged drug and ramiprilat and in feces (approximately 40%).1

Half-life

Triphasic; apparent elimination half-life of ramiprilat: Approximately 13–17 hours.1

Special Populations

In patients with Clcr <40 mL/minute per 1.73m2, urinary excretion of ramipril, ramiprilat, and their metabolites is decreased.1

Stability

Storage

Oral

Capsules

15–30 ºC.1

Mixtures of ramipril with applesauce, water, or apple juice (see Oral Administration under Dosage and Administration) are stable for 24 hours at room temperature and 48 hours when refrigerated.1

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ramipril

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

1.25 mg*

Altace

Pfizer

Ramipril Capsules

2.5 mg*

Altace

Pfizer

Ramipril Capsules

5 mg*

Altace

Pfizer

Ramipril Capsules

10 mg*

Altace

Pfizer

Ramipril Capsules

AHFS DI Essentials™. © Copyright 2024, Selected Revisions November 5, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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