Ramipril

Pharmacologic Category

Angiotensin-Converting Enzyme (ACE) Inhibitor; Antihypertensive

Dosing: Adult

Note: Consider discontinuation or dose reduction of concomitant diuretic when initiating ramipril. If diuretic cannot be discontinued or dose reduced, consider reduced initial ramipril dose. Monitor blood pressure closely until stabilized.

Heart failure post-myocardial infarction: Oral: Initial: 2.5 mg twice daily; may reduce dose to 1.25 mg twice daily for hypotension. Continue initial dose for one week then titrate upward every 3 weeks as tolerated to target dose of 5 mg twice daily.

Hypertension: Oral: Initial: 2.5 mg once daily; titrate dose based on patient response after 2 to 4 weeks up to 20 mg daily in 1 or 2 divided doses (ACC/AHA [Whelton 2017])

Reduction in risk of MI, stroke, and death from cardiovascular causes: Oral: Initial: 2.5 mg once daily for 1 week, then 5 mg once daily for the next 3 weeks, then increase as tolerated to maintenance dose of 10 mg once daily (may administer in divided doses in hypertensive or recently post-MI patients).

Heart failure with reduced ejection fraction (off-label use): Oral: Initial: 1.25 to 2.5 mg once daily; target dose: 10 mg once daily (ACC/AHA [Yancy 2013])

Dosage adjustment for patients with volume depletion: Initial: 1.25 mg once daily; titrate as tolerated to effect.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing; use with caution.

In the management of hypertension, consider lower initial doses and titrate to response (Aronow 2011).

Dosing: Renal Impairment: Adult

CrCl >40 mL/minute: No dosage adjustment necessary.

CrCl <40 mL/minute: Administer 25% of normal dose.

Heart failure post-MI: Initial: 1.25 mg once daily, may increase to 1.25 mg twice daily and then up to a maximum of 2.5 mg twice daily as tolerated.

Hypertension: Initial: 1.25 mg once daily, titrated as tolerated to effect; maximum: 5 mg/day.

Renal artery stenosis: Initial: 1.25 mg once daily; titrate as tolerated to effect.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling, however ramipril is primarily metabolized by hepatic esterases; patients with hepatic impairment could develop markedly elevated plasma levels of ramipril.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)

Use: Labeled Indications

Heart failure post-myocardial infarction: Treatment of heart failure (HF) after myocardial infarction (MI)

Guideline recommendations: The American College of Cardiology/American Heart Association (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

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]).

Reduction in risk of MI, stroke, and death from cardiovascular causes: To reduce the risk of MI, stroke, and death in patients ≥55 years of age at high risk of developing major cardiovascular events.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Heart failure with reduced ejection fractionLevel of Evidence [G]

Based on the American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Management of Heart Failure, ACE inhibitors, including ramipril, are effective and recommended in reducing morbidity and mortality in heart failure patients with reduced ejection fraction and current or prior symptoms even if they do not have a history of myocardial infarction.

Non–ST-elevation acute coronary syndromeLevel of Evidence [G]

Based on the 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 diseaseLevel of Evidence [G]

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.

ST-elevation acute coronary syndromeLevel of Evidence [G]

Based on the 2013 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, HF, or LVEF ≤40%, unless contraindicated. It is also reasonable to initiate an ACE inhibitor in all patients with STE-ACS.

Level of Evidence Definitions

Level of Evidence Scale

Class and Related Monographs

Angiotensin-Converting Enzyme Inhibitors

Clinical Practice Guidelines

Atrial Fibrillation:

AHA/ACC/HRS, "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," March 2014

Chronic Kidney Disease:

KDIGO 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease, January 2013

Coronary Artery Bypass Graft Surgery:

“2011 ACC/AHA Guideline for Coronary Artery Bypass Graft Surgery,” November 2011

AHA Scientific Statement, "Secondary Prevention After Coronary Artery Bypass Graft Surgery,” February 2015

Diabetes Mellitus:

American Diabetes Association, “Standards of Medical Care in Diabetes - 2019,” January 2019

Diabetes Canada, “Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada,” 2018

Heart Failure:

ACC/AHA, “2013 ACC/AHA Guideline for the Management of Heart Failure,” June 2013

ACC/AHA/HFSA, “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure,” May 2016

Canadian Cardiovascular Society, “2012 Heart Failure Management Guidelines Update: Focus on Acute and Chronic Heart Failure,” 2012

“HFSA 2010 Comprehensive Heart Failure Practice Guideline,” July 2010

Hypertension:

"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," November 2017.

AHA/ACC/ASH, “Treatment of Hypertension in Patients with Coronary Artery Disease: A Scientific Statement by the American Heart Association, American College of Cardiology and American Society of Hypertension,” May 2015

"ACC/AHA Expert Consensus Document on Hypertension in the Elderly," 2011

AHA/ACC/CDC, “AHA/ACC/CDC Science Advisory: An Effective Approach to High Blood Pressure Control” November 2013

ASH/ISH “Clinical Practice Guidelines for the Management of Hypertension in the Community: A Statement by the American Society of Hypertension and the International Society of Hypertension,” January 2014

Eighth Joint National Committee (JNC 8), "2014 Evidence-based Guideline for the Management of High Blood Pressure in Adults," December 2013. Note: Information contained within this monograph is pending revision based on these more recent guidelines.

“National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents,” May 2005

Ischemic Heart Disease:

ACC/AHA/AATS/PCNA/SCAI/STS, "2014 Focused Update of the Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease," July 2014

ACC/AHA/ACP/AATS/PCNA/SCAI/STS, “2012 Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease,” November 2012

AHA/ACC, "2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes,” September 2014.

ACC/AHA, “2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction,” December 2012

Ischemic Stroke:

AHA/ASA “2014 Guidelines for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack, May 2014

Prevention:

“AHA/ACC Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2011 Update,” November 2011

Surgery:

ACC/AHA, “2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery,” August 2014

Valvular Heart Disease:

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” March 2014

Administration: Oral

Swallow capsule whole; may open the capsule and the mix contents with 120 mL of water, apple juice, or applesauce.

Storage/Stability

Store at 15°C to 30°C (59°F to 86°F). Ramipril mixed with applesauce, apple juice, or water may be stored at room temperature for up to 24 hours or for up to 48 hours under refrigeration.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat high blood pressure.

• It is used to help heart function after a heart attack.

• It is used to lower the chance of heart attack, stroke, and death in some people.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache

• Cough

• Loss of strength and energy

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• High potassium like abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, or numbness or tingling feeling.

• Severe dizziness

• Passing out

• Persistent cough

• Severe abdominal pain

• Severe nausea

• Vomiting

• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to ramipril, other ACE inhibitors, or any component of the formulation; hereditary/idiopathic angioedema or history of angioedema related to previous treatment with an ACE inhibitor; concomitant use with aliskiren in patients with diabetes mellitus; concomitant use or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril).

Canadian labeling: Additional contraindications (not in US labeling): Hemodynamically relevant bilateral renal artery stenosis or unilateral in the single kidney; hypotensive or hemodynamically unstable states; concomitant use with aliskiren in patients with moderate to severe renal impairment (GFR <60 mL/minute/1.73 m²), hyperkalemia (>5 mMol/L) or congestive heart failure who are hypotensive; concomitant use with angiotensin II receptor blockers (ARBs) in patients with diabetes end organ damage, moderate to severe renal impairment (GFR <60 mL/minute/1.73 m²), hyperkalemia (>5 mMol/L) or congestive heart failure who are hypotensive; combination with extracorporeal treatments leading to contact of blood with negatively charged surfaces (dialysis or hemofiltration with certain high-flux [eg, polyacrylonitrile] membranes and low-density lipoprotein apheresis with dextran); pregnancy; breastfeeding.

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). Black patients and patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE inhibitor therapy may be at an increased risk. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) or neprilysin inhibitor (eg, sacubitril) therapy. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with previous angioedema associated with ACE inhibitor therapy is contraindicated.

• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, 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 (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and 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.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function (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 (ramipril is primarily metabolized by hepatic esterases and these patients could develop markedly elevated plasma levels of ramipril).

• 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 (ACC/AHA [Gersh 2011]).

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented unilateral or bilateral renal artery stenosis is present or suspected, 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 patients with renal impairment; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.

Concurrent drug therapy issues:

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

Special populations:

• Black patients: Effectiveness of ACE inhibitors is less in black patients than in non-blacks. 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 non-cardiac 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]).

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Due to frequent decreases in glomerular filtration (also creatinine clearance) with aging, elderly patients may have exaggerated responses to ACE inhibitors; differences in clinical response due to hepatic changes are not observed. ACE inhibitors may be preferred agents in elderly patients with CHF and diabetes mellitus. Diabetic proteinuria is reduced and insulin sensitivity is enhanced. In general, the side effect profile is favorable in the elderly and causes little or no CNS confusion; use lowest dose recommendations initially. Many elderly may be volume depleted due to diuretic use and/or blunted thirst reflex resulting in inadequate fluid intake.

The AHA/ACC/ASH 2015 scientific statement on the treatment of hypertension in patients with CAD warns to use caution to avoid decreases in DBP <60 mm Hg especially in patients >60 years of age since reduced coronary perfusion may occur. When lowering SBP in older hypertensive patients with wide pulse pressures, very low DBP values (<60 mm Hg) may result. In patients with obstructive CAD, clinicians should lower blood pressure slowly and carefully monitor for any untoward signs or symptoms, especially those resulting from myocardial ischemia and worsening heart failure (AHA/ACC/ASH [Rosendorff 2015]).

Pregnancy Considerations

Ramipril crosses the placenta.

Exposure to an angiotensin-converting enzyme (ACE) inhibitor during the first trimester of pregnancy may be associated with an increased risk of fetal malformations (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]); however, outcomes observed may also be influenced by maternal disease (ACC/AHA [Whelton 2017]).

[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. 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. 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 is also associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 203 2019).

When treatment of hypertension in pregnancy is indicated, ACE inhibitors should generally be avoided due to their adverse fetal events; use in pregnant women should only be considered for cases of hypertension refractory to other medications (ACOG 203 2019). ACE inhibitors are not recommended for the treatment heart failure in pregnancy (Regitz-Zagrosek [ESC 2018]).

ACE inhibitors should be avoided in sexually active females of reproductive potential not using effective contraception (ADA 2020). ACE inhibitors should generally be avoided for the treatment of hypertension in women planning a pregnancy; use should only be considered for cases of hypertension refractory to other medications (ACOG 203 2019).

Breast-Feeding Considerations

Ramipril and its metabolites were not detected in breast milk following a single oral dose of 10 mg. It is not known if multiple doses will produce detectable levels. Breastfeeding is not recommended by the manufacturer.

Lexicomp Pregnancy & Lactation, In-Depth

• Ramipril

Briggs' Drugs in Pregnancy & Lactation

• Ramipril

Adverse Reactions

Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with cardiac failure. However, the frequency of adverse effects associated with placebo is also increased in this population.

>10%:

Cardiovascular: Hypotension (11%)

Respiratory: Increased cough (7% to 12%)

1% to 10%:

Cardiovascular: Angina pectoris (≤3%), orthostatic hypotension (2%), syncope (≤2%)

Central nervous system: Headache (1% to 5%), dizziness (2% to 4%), fatigue (2%), vertigo (≤2%), noncardiac chest pain (1%)

Endocrine & metabolic: Hyperkalemia (1% to 10%)

Gastrointestinal: Nausea (≤2%), vomiting (≤2%)

Renal: Increased blood urea nitrogen (≤3%; transient increases may occur more frequently), increased serum creatinine (1% to 2%; transient increases may occur more frequently), renal insufficiency (1%)

Respiratory: Cough (1% to 10%)

<1%, postmarketing, and/or case reports: Abdominal pain, agitation, agranulocytosis, amnesia, anaphylactoid reaction, angioedema, anorexia, anxiety, arthralgia, arthritis, auditory impairment, bone marrow depression, cardiac arrhythmia, cerebrovascular disease, constipation, decreased hematocrit, decreased hemoglobin, depression, diaphoresis, diarrhea, drowsiness, dysgeusia, dyspepsia, dysphagia, dyspnea, edema, eosinophilia, epistaxis, erythema multiforme, gastroenteritis, hemolytic anemia, hepatitis, hypersensitivity reaction (fever, skin rash, urticaria), hyponatremia, impotence, increased serum transaminases, insomnia, malaise, myalgia, myocardial infarction, nervousness, neuralgia, neuropathy, onycholysis, palpitations, pancreatitis, pancytopenia, paresthesia, pemphigoid, pemphigus, proteinuria, purpura, seizure, sialorrhea, skin photosensitivity, Stevens-Johnson syndrome, symptomatic hypotension, thrombocytopenia, tinnitus, toxic epidermal necrolysis, tremor, visual disturbance, visual hallucination (Doane 2013), weight gain, xerostomia

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• ACE Inhibitor Allergy/Hypersensitivity

Toxicology

• Angiotensin-Converting Enzyme (ACE) Inhibitors

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk D: Consider therapy modification

Allopurinol: Angiotensin-Converting Enzyme Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk D: Consider therapy modification

Alteplase: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Alteplase. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

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

Angiotensin II: Angiotensin-Converting Enzyme Inhibitors may enhance the therapeutic effect of Angiotensin II. Risk C: 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. Risk D: Consider therapy modification

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

Aprotinin: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

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

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

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

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

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk X: Avoid combination

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

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

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

Drospirenone: Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Drospirenone. Risk C: Monitor therapy

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

Eplerenone: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

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

Ferric Gluconate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: 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. Risk C: 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. Risk C: 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. Risk C: 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). Risk D: Consider therapy modification

Heparin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

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

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

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

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

Icatibant: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: 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. Risk D: 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. Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

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

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

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

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

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: 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. Risk C: 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. Risk D: Consider therapy modification

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

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

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

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

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

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

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

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Racecadotril: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased with this combination. Risk C: Monitor therapy

Ranolazine: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: 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. Risk X: Avoid combination

Salicylates: May enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: 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. Risk D: Consider therapy modification

Tacrolimus (Systemic): Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy

Telmisartan: May enhance the adverse/toxic effect of Ramipril. Telmisartan may increase the serum concentration of Ramipril. Concentrations of the active metabolite, ramiprilat, may also be increased. Risk X: Avoid combination

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

TiZANidine: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

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

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

Urapidil: May interact via an unknown mechanism with Angiotensin-Converting Enzyme Inhibitors. Management: Avoid concomitant use of urapidil and angiotensin-converting enzyme (ACE) inhibitors. Risk D: Consider therapy modification

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

Test Interactions

Positive Coombs' [direct]; may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent; may lead to false-negative aldosterone/renin ratio (ARR) (Funder 2016)

Genes of Interest

• Angiotensin I Converting Enzyme 1
• Angiotensin II Receptor, Type 1
• Angiotensinogen (Serpin Peptidase Inhibitor, Clade A, Member 8)
• Bradykinin Receptor B2
• Cytochrome P450 11B2

Monitoring Parameters

Blood pressure; BUN, serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential.

In heart failure post-myocardial infarction patients, monitor for at least 2 hours after initial dose and for at least an additional hour after blood pressure has stabilized.

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 (ACC/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 atherosclerotic cardiovascular disease (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 2019):

Patients 18 to 65 years of age, without ASCVD, and 10-year ASCVD risk <15%: Target blood pressure <140/90 mm Hg is recommended.

Patients 18 to 65 years of age and known ASCVD or 10-year ASCVD risk >15%: Target blood pressure <130/80 mm Hg may be appropriate if it can be safely attained.

Patients >65 years of age (healthy or complex/intermediate health): Target blood pressure <140/90 mm Hg is recommended.

Patients >65 years of age (very complex/poor health): Target blood pressure <150/90 mm Hg is recommended.

Advanced Practitioners Physical Assessment/Monitoring

Obtain BUN, serum creatinine, serum potassium, and CBC with differential (patients with renal impairment or collagen vascular disease). Monitor blood pressure. Assess other medicines patient may be taking; alternate therapy or dosage adjustments may be needed. Assess for signs of angioedema. Assess pregnancy status and ensure proper use of birth control prior to therapy.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor blood pressure. Monitor for signs of angioedema. Instruct women of child-bearing age to notify provider immediately for pregnancy.

Dosage Forms: US

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

Capsule, Oral:

Altace: 1.25 mg

Altace: 2.5 mg [contains fd&c red #40, fd&c yellow #10 (quinoline yellow)]

Altace: 5 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Altace: 10 mg [contains brilliant blue fcf (fd&c blue #1)]

Generic: 1.25 mg, 2.5 mg, 5 mg, 10 mg

Dosage Forms: Canada

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

Capsule, Oral:

Altace: 1.25 mg, 2.5 mg

Altace: 5 mg, 10 mg [contains fd&c blue #2 (indigotine)]

Altace: 15 mg [contains brilliant blue fcf (fd&c blue #1)]

Generic: 1.25 mg, 2.5 mg, 5 mg, 10 mg, 15 mg

Tablet, Oral:

Ramace: 2.5 mg [DSC]

Generic: 1.25 mg, 2.5 mg, 5 mg, 10 mg

Anatomic Therapeutic Chemical (ATC) Classification

• C09AA05

Generic Available (US)

Yes

Pricing: US

Capsules (Altace Oral)

1.25 mg (per each): $6.06

2.5 mg (per each): $7.16

5 mg (per each): $7.51

10 mg (per each): $8.79

Capsules (Ramipril Oral)

1.25 mg (per each): $1.46 - $1.53

2.5 mg (per each): $1.71 - $1.81

5 mg (per each): $1.80 - $1.89

10 mg (per each): $2.10 - $2.22

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Ramipril is an ACE inhibitor which prevents the formation of angiotensin II from angiotensin I and exhibits pharmacologic effects that are similar to captopril. Ramipril must undergo enzymatic saponification by esterases in the liver to its biologically active metabolite, ramiprilat. The pharmacodynamic effects of ramipril result from the high-affinity, competitive, reversible binding of ramiprilat to angiotensin-converting enzyme, thus preventing the formation of the potent vasoconstrictor angiotensin II. This isomerized enzyme-inhibitor complex has a slow rate of dissociation, which results in high potency and a long duration of action; a CNS mechanism may also be involved in the 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

Pharmacodynamics/Kinetics

Onset of action: 1-2 hours

Duration: 24 hours

Absorption: Well absorbed (50% to 60%)

Distribution: Plasma levels decline in a triphasic fashion; rapid decline is a distribution phase to peripheral compartment, plasma protein and tissue ACE (half-life: 2-4 hours); second phase is an apparent elimination phase representing the clearance of free ramiprilat (half-life: 9-18 hours); and final phase is the terminal elimination phase representing the equilibrium phase between tissue binding and dissociation

Protein binding: Ramipril: 73%; Ramiprilat: 56%

Metabolism: Hepatic to the active form, ramiprilat

Bioavailability: Ramipril: 28%; Ramiprilat: 44%

Half-life elimination: Ramiprilat: Effective: 13-17 hours; Terminal: >50 hours

Time to peak, serum: Ramipril: ~1 hour; Ramiprilat: 2-4 hours

Excretion: Urine (60%) and feces (40%) as parent drug and metabolites

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: In patients with CrCl <40 mL/minute, peak levels of metabolite approximately doubled. AUC was 3 to 4 times larger. Urinary excretion of metabolite is reduced. Higher peak and trough ramiprilat levels.

Hepatic function impairment: Slowed metabolism of ramiprilat. Ramipril plasma levels increase about 3-fold.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Patients may experience orthostatic hypotension as they stand up after treatment; especially if lying in dental chair for extended periods of time. Use caution with sudden changes in position during and after dental treatment.

An angiotensin-converting enzyme (ACE) Inhibitor cough is a dry, hacking, nonproductive cough that can potentially interfere with longer dental procedures if patient has this side effect.

Effects on Bleeding

No information available to require special precautions

Related Information

• Angiotensin Agents

FDA Approval Date

January 28, 1991

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Brand Names: International

Acovil (ES); Acuril (LB); Altace (VE); Amipril (PH); Amivan (PH); Ampril (HR, LV); Anexia (ID); Anhiram (UA); Bigastus (EG); Cardace (ID, IN, LK, LV); Cardika (LK); Cardipril (UA); Cartace (BD); Corpril (EG, TH); Delix (DE, TR); Hartil (RU, UA); Heartprilprotect (KR); Hyperil (ID); Hypren (AT); Intemipril (CR, DO, GT, HN, NI, PA, SV); Lostapres (AR); Naprix (BR); Normopril (LB); Piramil (EE); Polapril (LV); Pramace (SE); Pril (BD); Prilace (AU); Primace (BD); Prohytens (ID); Quark (IT); Ramace (AU, CR, DK, DO, FI, GT, HN, LU, NI, NZ, PA, SG, SV); Ramey (TW); Ramicard (BD); Ramicor (PY); Ramily (TW); Ramipres (CL); Ramiprin (KR); Ramipro (PH); Ramitace (TW); Ramitens (IL); Ramixal (ID); Rampil (ZA); Ramtace (MY); Redutens (ID); Servace (LK); Sipo (TW); Syntace (TW); Topril (ZW); Triatec (BR, CH, CN, DK, FR, GR, ID, IE, IL, IT, NO, PT, SE, VN); Triateckit (FR); Triltec (LB, QA); Tripril (MY); Tritace (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BM, BS, BZ, CI, CL, CO, CZ, DK, EC, EG, ET, GB, GH, GM, GN, GY, HK, HR, HU, JM, JO, KE, KR, KW, LB, LR, LU, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NZ, PH, PK, PL, PR, PY, QA, SC, SD, SI, SK, SL, SN, SR, TH, TN, TT, TW, TZ, UA, UG, UY, ZM, ZW); Tritace Protect (KR); Tryzan (AU); Unipril (BD, IT); Vaspril (TH); Vesdil (DE); Zenra (RO)

Last Updated 2/22/20