VA Class:CV800

AHFS Class:

• Angiotensin-Converting Enzyme Inhibitors 24:32.04

Generic Name(s):

• Ramipril

• Ramiprilat

Chemical Name:

• [2 S -[1[ R *( R *)],2α,3aβ,6aβ]]-1-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropy l]octahydrocylopenta[ b ]pyrrole-2-carboxylic acid

• [2 S -[1[ R *( R *)],2α,3aβ,6aβ]]-1-[2-[(1-Carboxy-3-phenylpropyl)amino]-1-oxopropyl]octahyd rocyclopenta[ b ]pyrrole-2-carboxylic acid

Molecular Formula:

• C₂₁H₂₈N₂O₅

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor.1,2,3

Ramipril is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension.1,600,1200 Ramipril also is used to reduce the risk of mortality (mainly cardiovascular mortality) following myocardial infarction (MI) in hemodynamically stable patients who have demonstrated clinical signs of heart failure within a few days following acute MI; ramipril therapy 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 In addition, ramipril has been shown to reduce the rate of death, MI, and stroke in patients at high risk for cardiovascular events†.47,48

Because captopril, another angiotensin-converting enzyme (ACE) inhibitor, may cause serious adverse effects (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease)1 or in patients receiving immunosuppressive therapy,5,6 the possibility that similar adverse effects may occur with ramipril should be considered since current evidence is insufficient to rule out such risk.1 (See Cautions: Hematologic Effects, in Captopril 24:32.04.)

Hypertension

Ramipril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1,2,4,1200 ACE inhibitors are considered one of several preferred antihypertensive drugs 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 (See Uses: Hypertension, in Captopril 24:32.04.)

ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as heart failure, ischemic heart disease, diabetes mellitus, chronic kidney disease (CKD), or cerebrovascular disease or following MI.501,502,504,523,524,525,526,527,534,535,536,543,1200,1214,1215 (See Uses: Hypertension in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.)

In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.1200 However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).1200,1218 Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.1218 Because of similar efficacy and a lower frequency of adverse effects, some experts believe that an angiotensin II receptor antagonist should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.1218

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors.14,67,68,86,87,501,504,1200 Although ACE inhibitors have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low renin hypertension.1,14,15,67,68 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.1,68,1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.)

For additional information on the role of ACE inhibitors in the management of hypertension, see Uses in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Heart Failure After Acute Myocardial Infarction

Ramipril is used to reduce the risk of mortality (mainly cardiovascular mortality) following MI in hemodynamically stable patients who have demonstrated clinical signs of heart failure within a few days following acute MI; ramipril therapy also may reduce the rate of heart failure-associated hospitalization and progression to severe and/or resistant heart failure.1,2,12,18,21,24,27,28,524 In these patients, when compared with those receiving placebo, ramipril therapy initiated on average 5 (range: 2-9) days after acute MI reduced risk of mortality from any cause by approximately 27% (90% of mortality was cardiovascular, mainly sudden death); risk of progression to severe heart failure and heart failure-associated hospitalization were reduced by 23 and 26%, respectively.1,21,27,28,524 In addition, ramipril reduced risk of mortality combined with other events (e.g., reinfarction, stroke, development of severe heart failure) by 19%.12 This evidence of efficacy was obtained from a large, controlled, long-term (average: 15 months; range: 6-46 months) study (the Acute Infarction Ramipril Efficacy; AIRE).1,2,12 Benefits of ramipril were observed by day 30 of drug therapy and were not affected by gender, exact timing of initiation of drug therapy, or by concomitant drugs (e.g., aspirin, nitrates, β-adrenergic blocking agents [β-blockers], thrombolytic agents, calcium-channel blocking agents, cardiac glycosides); however, such benefits appeared to be increased in patients 65 years and older and in those receiving diuretics.1,12 Ramipril did not appear to reduce the rates of reinfarction, although there was a trend to fewer such events when compared with placebo.12

Studies with various ACE inhibitors have shown that these drugs reduce fatal and nonfatal cardiovascular events in patients with recent MI.527,803,1100 The magnitude of benefit appears to be greatest in certain high-risk patients (e.g., those with an anterior infarct, ejection fraction of 40% or less, heart failure, prior infarction, or tachycardia).527,805,1100 In addition to their effects on mortality, ACE inhibitors also are used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular “remodeling”) following acute MI.31,32,33,34,35,36,37 Evidence regarding the efficacy of such therapy has been somewhat conflicting,12,21,23,24,25,26,27,28,31,32,33,34,35,36,37 particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline left ventricular dysfunction.19,20,21,22,23,24,25,26,27,29,30,31,32,34,35,36,37 (See Uses: Left Ventricular Dysfunction After Acute Myocardial Infarction in Enalaprilat/Enalapril 24:32.04.) However, the preponderance of evidence has shown a benefit of early oral therapy with ACE inhibitors, even in patients with no baseline dysfunction.1,12,19,20,21,22,23,24,25,26,27,28,29,30,31,32,34,35,36,37

Current expert guidelines recommend the use of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarction, heart failure, or ejection fraction of 40% or less who do not have any contraindications (e.g., hypotension, shock, renal dysfunction).527 While early treatment within the first 24 hours of MI has been shown to be beneficial, ACE inhibitors should be used with caution (and with gradual upward titration) during the initial postinfarction period because of the possibility of hypotension or renal dysfunction.527,1100 ACE inhibitor therapy generally should be continued indefinitely in all patients with left ventricular dysfunction or other compelling indications for use (e.g., hypertension, diabetes mellitus, CKD).525,1100 The benefits of long-term ACE inhibitor therapy are less certain in low-risk patients who have undergone revascularization and are receiving aggressive antilipemic therapy.527

Prevention of Major Cardiovascular Events

Ramipril may reduce the rate of death, MI, and stroke in patients 55 years of age and older who are at high risk for cardiovascular events (e.g., those with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus, in addition to at least one other cardiovascular risk factor, including hypertension, elevated serum total cholesterol and/or decreased high-density lipoprotein [HDL]-cholesterol concentrations, smoking, or documented microalbuminuria) and who are not known to have low left ventricular ejection fraction (LVEF) or heart failure.1,47,48 Ramipril may be used concomitantly with antihypertensive, antiplatelet, or antilipemic drugs.1 Results of a randomized, multicenter, double-blind, placebo-controlled study (Heart Outcomes Prevention Evaluation [HOPE]) of approximately 5 years' duration in more than 9000 patients 55 years of age or older with a history of coronary artery disease, stroke, peripheral vascular disease, and at least one other cardiovascular risk factor (see above) indicate that ramipril (10 mg daily after an initial dosage of 2.5 mg daily for 1 week followed by 5 mg daily for 3 weeks) reduced the risk of cardiovascular death, stroke, and MI by about 25, 32, and 20%, respectively, compared with placebo.47,48 When compared with placebo, the drug also reduced the risk of cardiac arrest and heart failure by approximately 34 and 21%, respectively, and the need for coronary revascularization procedures by 15%.47,48 The exact mechanism of the beneficial effects of ramipril in high-risk patients for cardiovascular events has not been fully elucidated, but it appears that ACE inhibitors may antagonize the direct effects of angiotensin II thereby preventing the proliferation of vascular smooth muscle cells and rupture of fibrous plaques.47,50 ACE inhibitors also may improve vascular endothelial function, reduce left ventricular hypertrophy, and enhance fibrinolysis.47,50

In addition to these beneficial cardiovascular effects, a reduction in the incidence of diabetic complications was reported in 6.2% of patients receiving ramipril compared with 7.4% of those receiving placebo.47,48 New diagnosis of diabetes was reported in fewer patients receiving ramipril compared with those receiving placebo.47 Although the exact mechanism of the endocrine effects of ramipril is not known, it has been suggested that ACE inhibitors may prevent diabetic complications and new diagnosis of diabetes by improving insulin sensitivity and blood flow to the pancreas and by decreasing hepatic clearance of insulin.47,49 In addition, results of other studies indicate that in patients with type 2 diabetes mellitus, intensive control of blood pressure (e.g., an approximate target systolic pressure of less than 150 mm Hg and diastolic pressure of less than 85 mm Hg) using an ACE inhibitor (e.g., captopril) or a β-blocker (e.g., atenolol) resulted in a reduction of development or progression of complications of diabetes (e.g., death related to diabetes, stroke, heart failure, microvascular disease).52,53,54,55,57,58,59,60

In the HOPE study, reduction of cardiovascular risk factors was observed within 1 year of initiation of ramipril therapy and continued throughout the study (approximately 5 years).47 Because interim analysis of this study after about 5 years revealed a clear evidence of a beneficial effect of ramipril, the study was discontinued.47,48

Heart Failure

ACE inhibitors have been used in the management of heart failure†, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers.70,71,72,73,74,524,800

Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524,800,701,703 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.524,800 Experts recommend that all asymptomatic patients with reduced LVEF (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality.524 In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.800 While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction,524 some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients.702,800 ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [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.800 However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised.800 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.800 For additional information on the use of ACE inhibitors in the management of heart failure, see Uses: Heart Failure, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04. For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.

Diabetic Nephropathy

Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria†,81,82,83,84,85,1232 and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion.535,536,1232 The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.77 For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see Diabetic Nephropathy under Uses: Nephropathy, in Captopril 24:32.04.

Administration

Ramipril is administered orally.1 The rate but not the extent of GI absorption of the drug may be reduced by administration with food.1,2 Ramipril capsules usually are swallowed whole.1 However, if needed such capsules also may be opened and contents sprinkled in a small amount (about 120 mL) of applesauce or mixed in 120 mL of water or apple juice.1 To ensure that no drug is lost, the entire mixture should be consumed.1 These mixtures are stable for 24 hours at room temperature and 48 hours when refrigerated.1 The manufacturers state that serum ramiprilat concentrations are not affected when contents of ramipril capsules are mixed in applesauce or dissolved in water or apple juice.1

Dosage

Dosage of ramipril must be adjusted according to patient tolerance and response.1 Because of the risk of inducing hypotension, initiation of ramipril therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances.1 If therapy is initiated in a patient already receiving a diuretic, symptomatic hypotension may occur following the initial dose of the angiotensin-converting enzyme (ACE) inhibitor.1,2 To minimize the possibility of hypotension, especially in patients in whom diuretic therapy was recently initiated, it is recommended that diuretic therapy be discontinued, the diuretic dosage decreased, or salt intake increased, if possible, before initiating ramipril.600 If such changes are not possible, ramipril therapy should be initiated at a reduced dosage of 1.25 mg once daily.600 (See Cardiovascular Effects under Warnings/Precautions: Warnings, in Cautions.) For additional information on initiating ramipril in patients receiving diuretic therapy, see the disease-specific dosage sections in Dosage and Administration. Hypotension does not preclude the administration of subsequent doses of the drug, provided the hypotension has been managed effectively.1

Hypertension

Usual Dosage

For the management of hypertension in adults not receiving a diuretic, the manufacturer states that the usual initial dosage of ramipril is 2.5 mg once daily.600 In patients currently receiving a diuretic, an initial ramipril dosage of 1.25 mg once daily is recommended; however, discontinuance or dosage reduction of the diuretic or an increase in salt intake is preferred.600 (See the introductory discussion under Dosage and Administration: Dosage.) Subsequent dosage of ramipril should be adjusted according to the patient's blood pressure response.600 If the blood pressure response diminishes toward the end of the dosing interval during once-daily administration, increasing the dosage or giving the drug in 2 divided doses daily should be considered.600 The usual maintenance dosage recommended by the manufacturer and some experts in adults is 2.5-20 mg daily, given as a single dose or in 2 divided doses.600,1200,1200

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with ACE inhibitor monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with ramipril, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 a 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Heart Failure After Acute Myocardial Infarction

When used after myocardial infarction (MI) in adults with clinical signs of heart failure, the manufacturer recommends an initial ramipril dosage of 2.5 mg twice daily, but if hypotension occurs, dosage should be reduced to 1.25 mg twice daily.1 Some clinicians recommend initiation of therapy within the first 24 hours following MI.527 After one week at the initial dosage, therapy is then titrated as tolerated, at intervals of about 3 weeks, to a target daily dosage of 5 mg twice daily.1 After the initial dose of ramipril, the patient should be observed closely for at least 2 hours and for at least 1 additional hour after blood pressure has stabilized.1 To minimize the likelihood of hypotension, the dosage of any concomitant diuretic should be reduced, if possible.1 The appearance of hypotension after the initial dose of ramipril does not preclude subsequent carefully titrated doses of the drug after the hypotension has been effectively managed.1 Dosage should be adjusted carefully under close medical supervision in patients with heart failure because of the risk of hypotension; such patients should be followed closely for at least 2 weeks after initiation of ramipril therapy or any increase in ramipril or diuretic dosage.600

Prevention of Major Cardiovascular Events

For reduction in the risk of MI, stroke, and death from cardiovascular causes, the manufacturers recommend that patients receive 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.1 In patients with hypertension or those with recent MI, dosage of ramipril may be given in divided doses.1

Heart Failure

In patients with prior or current symptoms of chronic heart failure and reduced LVEF (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage C heart failure†), ACCF and AHA recommend an initial ramipril dosage of 1.25-2.5 mg once daily.524 The dosage should be slowly titrated upward as tolerated to dosages that have been shown to reduce the risk of cardiovascular events in clinical trials; if such target dosages cannot be achieved or are poorly tolerated, ACCF and AHA state that intermediate doses should be used.524 ACCF and AHA recommend a maximum ramipril dosage of 10 mg once daily for patients with ACCF/AHA stage C heart failure.524

Special Populations

If ramipril is used in patients with impaired renal function, dosage must be modified in response to the degree of renal impairment, and as with other ACE inhibitors, the theoretical risk of neutropenia must be considered.1,2,3 In adults with creatinine clearances less than 40 mL/minute, 25% of the usual doses are expected to induce full therapeutic concentrations of ramiprilat.1 For the management of hypertension in these patients, the usual initial dosage of ramipril is 1.25 mg once daily.1 Subsequent dosage should be titrated according to individual tolerance and blood pressure response, up to a maximum of 5 mg daily.1 In patients with heart failure following acute MI and who have creatinine clearances less than 40 mL/minute, the usual initial dosage of ramipril is 1.25 mg once daily; dosage may be increased to 1.25 mg twice daily.1 Subsequent dosage should be titrated according to individual clinical response and tolerance up to a maximum dosage of 2.5 mg twice daily.1

Patients with known or suspected renal artery stenosis should receive an initial ramipril dosage of 1.25 mg once daily; subsequent dosage should be adjusted based on blood pressure response.600

Since ramipril is primarily metabolized by hepatic esterases to ramiprilat (its active moiety), hepatic impairment may result in increased ramipril plasma concentrations.1 In addition, the renin-angiotensin-aldosterone (RAA) system (see Renal Effects under Warnings/Precautions: General Precautions, in Cautions) may be activated in hypertensive patients with severe hepatic impairment (e.g., severe liver cirrhosis and/or ascites).1 However, the manufacturers make no specific recommendations regarding dosage adjustment in patients with hepatic impairment.1

For additional information on initiating and adjusting ramipril dosage in the management of hypertension, including recommendations for blood pressure monitoring, see Dosage: Hypertension, under Dosage and Administration, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.

Contraindications

History of angioedema related to previous angiotensin-converting enzyme (ACE) inhibitor treatment.1

Known hypersensitivity to ramipril, other ACE inhibitors, or any ingredient in the formulation.1

Concomitant use of ramipril and aliskiren in patients with diabetes mellitus.600 (See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)

Warnings/Precautions

Warnings

Hypotension

Like other ACE inhibitors, ramipril rarely is associated with hypotension in patients with uncomplicated hypertension.1 Symptomatic hypotension may occur; patients at particular risk include those with severe volume and/or salt depletion secondary to prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.1 Volume and/or salt depletion should be corrected before starting ramipril therapy.1

Marked hypotension may occur in patients with heart failure (with or without associated renal impairment), which may be associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death.1 In patients with heart failure, ramipril therapy should be started under close medical supervision, and patients should be followed closely for at least 2 weeks after initiation of ramipril or diuretic therapy or dosage adjustment of either drug.1 (See Dosage and Administration: Dosage.)

If hypotension occurs, the patient should be placed in the supine position, and if necessary, an IV infusion of 0.9% sodium chloride injection to expand fluid volume should be administered.1 Ramipril therapy usually may be continued following restoration of blood pressure and volume.1

Hematologic Effects

Neutropenia/agranulocytosis, anemia, leukopenia, thrombocytopenia, pancytopenia may occur in patients receiving ACE inhibitors, particularly in patients with renal impairment (especially those with concomitant collagen vascular disease [e.g., systemic lupus erythematosus, scleroderma]).1 Monitoring of leukocytes in patients with collagen vascular disease, especially if renal impairment exists, should be considered.1

Fetal/Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters.1,39,40,41,42,43,44,45,46 ACE inhibitors also 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.1,89 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.44,46 For additional information on the risk of ACE inhibitors during pregnancy, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04.

Hepatic Effects

Rare ACE inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice may occur; may progress to fulminant hepatic necrosis and is potentially fatal.1 Patients receiving an ACE inhibitor, including ramipril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the drug and receive appropriate monitoring. 1

Sensitivity Reactions

Sensitivity reactions, including anaphylactic reactions and angioedema (including laryngeal or tongue edema) are potentially fatal.1 Head and neck angioedema involving the tongue, glottis, or larynx may cause airway obstruction.1 If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, ramipril should be discontinued and appropriate therapy (e.g., epinephrine) should be initiated immediately.1

Intestinal angioedema (occasionally without a prior history of facial angioedema or elevated serum levels of complement 1 [C1] esterase inhibitor) also has been reported in patients receiving ACE inhibitors.1 Intestinal angioedema, which frequently presents as abdominal pain (with or without nausea or vomiting), usually is diagnosed by abdominal CT scan, ultrasound, or surgery;1 symptoms usually have resolved after discontinuance of the ACE inhibitor.1 Intestinal angioedema should be considered in the differential diagnosis of patients who develop abdominal pain during therapy with an ACE inhibitor.1

Patients receiving concomitant mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus) may be at increased risk for angioedema.600

Life-threatening anaphylactoid reactions have been reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.1 When ACE inhibitors were temporarily discontinued before desensitization with the venom, anaphylactoid reactions did not recur; however, such reactions recurred after inadvertent rechallenge.1 Anaphylactoid reactions have been reported following initiation of hemodialysis that used a high-flux membrane in patients receiving an ACE inhibitor.1 In addition, anaphylactoid reactions have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption.1

General Precautions

Renal Effects

Inhibition of the renin-angiotensin-aldosterone (RAA) system may cause renal impairment and rarely renal failure and/or death in susceptible patients (e.g., those whose renal function depends on the activity of the RAA system such as patients with severe heart failure).1

Deterioration in renal function, manifested as transient increases in BUN and serum creatinine concentrations may occur following administration of ACE inhibitor therapy, particularly in hypertensive patients with unilateral or bilateral renal-artery stenosis, preexisting renal impairment, or concomitant diuretic therapy.1 This effect was usually reversible following discontinuance of ACE inhibitor and/or diuretic therapy.1 Renal function should be monitored closely during the first few weeks of therapy and periodically thereafter in such patients.1,97

Effects on Potassium

Hyperkalemia can develop, especially in those 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

Cough

Persistent and nonproductive; resolves after drug discontinuance.1

Surgery/Anesthesia

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension.1 Hypotension in such patients may be corrected by volume expansion.1

Specific Populations

Pregnancy

Category C (first trimester); Category D (second and third trimesters).1 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Ramipril and its metabolites were undetectable in breast milk following a single 10-mg oral dose of the drug in nursing women; however, milk concentrations resulting from multiple doses of the drug have not been determined.1 Because of the potential for serious adverse reactions from ramipril in nursing infants, the manufacturers state that women receiving the drug should not breast-feed.1

Pediatric Use

The manufacturers state that safety and efficacy of ramipril in children younger than 18 years of age have not been established.1,97 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 Increased ramiprilat plasma concentrations and area under the concentration-time curve (AUC) have been reported in some geriatric patients.1

Renal Impairment

Renal function may decrease with ACE inhibitor therapy in susceptible patients.1 Use with caution in those with renal impairment.1 (See Dosage and Administration: Special Populations and also under Warnings/Precautions: General Precautions, Renal Effects, in Cautions.)

Hepatic Impairment

Use with caution. (See Dosage and Administration: Special Populations.)

Black Patients

ACE inhibitors not as effective.1 (See Uses: Hypertension.)

Common Adverse Effects

Adverse effects reported in 1% or more of patients receiving ramipril and considered possibly or probably related to treatment include asthenia/fatigue,1 hypotension,1 postural hypotension,1 increased cough,1 dizziness,1 headache,1 angina pectoris,1 nausea,1 syncope,1 vomiting,1 vertigo,1 abnormal kidney function,1 and diarrhea.1

Drugs that Block the Renin-Angiotensin System

Increased risk of renal impairment, hyperkalemia, and hypotension with concomitant use of other drugs that block the renin-angiotensin system (e.g., aliskiren, angiotensin II receptor antagonists); when ramipril is used concomitantly with such drugs, blood pressure, renal function, and serum concentrations of electrolytes should be monitored closely. 600 Concomitant use of ramipril and aliskiren is contraindicated in patients with diabetes mellitus; in addition, such concomitant use should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m²).550,600 (See Cautions in Aliskiren Hemifumarate 24:32.40.)

Drugs Increasing Serum Potassium Concentration

Potential pharmacologic interaction (additive hyperkalemic effect).1 Includes potassium-sparing diuretics, potassium supplements, and other drugs that can cause hyperkalemia.1

Diuretics

Potential pharmacokinetic and pharmacologic interaction (hypotensive effect).1

Lithium

Potential pharmacokinetic interaction (increased lithium concentrations and clinical toxicity).1

mTOR Inhibitors

Patients receiving concomitant mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus) may be at increased risk for angioedema.600

Nonsteroidal Anti-inflammatory Agents

Potential pharmacologic interaction (decreased renal function and increased serum potassium concentrations).1 (See Drug Interactions in Captopril 24:32.04.)

Description

Ramipril is an angiotensin-converting enzyme (ACE, bradykininase, kininase II) inhibitor.1,2,3 Unlike captopril or lisinopril but similar to benazepril, enalapril, fosinopril, moexipril, perindopril, quinapril, and trandolapril, ramipril is a prodrug and has little pharmacologic activity until hydrolyzed in the liver to ramiprilat.1,2,3,90,91,92,93,94,95,96 Like benazepril, enalapril, fosinopril, lisinopril, moexipril, and quinapril but unlike captopril, ramipril does not contain a sulfhydryl group.1,2,3

Advice to Patients

Risk of angioedema, anaphylactoid, and other sensitivity reactions; importance of discontinuing the drug and immediately reporting suggestive manifestation (e.g., edema of face, eyes, lips, or tongue; swallowing or breathing with difficulty) to a clinician.1

Risk of hypotension (e.g., lightheadedness, syncope), especially during initial therapy or with volume depletion secondary to excessive perspiration, vomiting, or diarrhea.1 Importance of adequate fluid intake.1 Importance of discontinuing drug and contacting clinician if symptoms of syncope occur.1

Importance of contacting a clinician promptly if manifestations of infection or neutropenia (e.g., sore throat, fever) develop.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Risk of hyperkalemia.1 Importance of avoiding the use of potassium supplements or salt substitutes containing potassium without consultation with a clinician.1

Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1,89 Risk of use during first, second, and third trimesters of pregnancy.1,88,89

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturers' labelings should be consulted. It is essential that the manufacturers' labelings be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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