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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(RA mi pril)
Generic Available (U.S.)
Yes
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hypertension, alone or in combination with thiazide diuretics; treatment of left ventricular dysfunction after MI; to reduce risk of MI, stroke, and death in patients at increased risk for these events
Use: Unlabeled
Treatment of heart failure; to delay the progression of nephropathy and reduce risks of cardiovascular events in hypertensive patients with type 1 or 2 diabetes mellitus
Pregnancy Risk Factor
D
Pregnancy Considerations
[U.S. 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. Ramipril crosses the placenta; teratogenic effects may occur following maternal use during pregnancy. 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. Their use in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant. ACE inhibitors are not recommended during pregnancy to treat maternal hypertension or heart failure. Use of an ACE inhibitor should also be avoided in any woman of reproductive age. Women who are planning a pregnancy should be considered for other medication options if an ACE inhibitor is currently prescribed or the ACE inhibitor should be discontinued as soon as possible once pregnancy is detected. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria.
Lactation
Excretion in breast milk unknown/not recommended
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. Breast-feeding is not recommended by the manufacturer.
Contraindications
Hypersensitivity to ramipril or any component of the formulation; prior hypersensitivity (including angioedema) to ACE inhibitors
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
Concerns related to adverse effects:
• Angioedema: At any time during treatment (especially following first dose) angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). African-Americans and patients with idiopathic or hereditary angioedema may be at an increased risk. 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; 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 1-4 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.
• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, 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.
• Neutropenia/agranulocytosis: Another ACE Inhibitor, captopril, has been associated with rare cases of agranulocytosis, neutropenia, or leukopenia with myeloid hypoplasia. 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.
• 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 glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.
Disease-related concerns:
• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.
• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.
• 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.
• Renal artery stenosis: Use ramipril with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution in pre-existing renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.
Concurrent drug therapy issues:
• Angiotensin receptor blockers: Concurrent use of angiotensin receptor blockers may increase the risk of clinically-significant adverse events (eg, renal dysfunction, hyperkalemia). Concurrent use with telmisartan is not recommended.
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
Other warnings/precautions:
• Surgery: 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.
Adverse Reactions
Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with CHF. However, the frequency of adverse effects associated with placebo is also increased in this population.
>10%: Respiratory: Cough increased (7% to 12%)
1% to 10%:
Cardiovascular: Hypotension (11%), angina (up to 3%), postural hypotension (2%), syncope (up to 2%)
Central nervous system: Headache (1% to 5%), dizziness (2% to 4%), fatigue (2%), vertigo (up to 2%)
Endocrine & metabolic: Hyperkalemia (1% to 10%)
Gastrointestinal: Nausea/vomiting (1% to 2%)
Neuromuscular & skeletal: Chest pain (noncardiac) (1%)
Renal: Renal dysfunction (1%), serum creatinine increased (1% to 2%), BUN increased (<1% to 3%); transient increases of creatinine and/or BUN may occur more frequently
Respiratory: Cough (estimated 1% to 10%)
<1%: Agranulocytosis, abdominal pain, amnesia, anaphylactoid reaction, angioedema, anorexia, anxiety, arrhythmia, arthralgia, arthritis, bone marrow depression, cerebrovascular events, constipation, convulsions, decreased hematocrit, decreased hemoglobin, depression, diarrhea, dyspepsia, dysphagia, dyspnea, edema, eosinophilia, epistaxis, erythema multiforme, gastroenteritis, hearing loss, hemolytic anemia, hepatitis, hypersensitivity reactions (fever, rash, urticaria), hyponatremia, impotence, increased diaphoresis, increased salivation, insomnia, malaise, myalgia, MI, nervousness, neuralgia, neuropathy, onycholysis, palpitation, pancreatitis, pancytopenia, paresthesia, pemphigoid, pemphigus, photosensitivity, proteinuria, purpura, somnolence, Stevens-Johnson syndrome, symptomatic hypotension, taste disturbance, thrombocytopenia, tinnitus, toxic epidermal necrolysis, transaminases increased, tremor, vision disturbances, weight gain, xerostomia
Postmarketing and/or case reports: Agitation
Worsening of renal function may occur in patients with bilateral renal artery stenosis or in hypovolemia. In addition, a syndrome which may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia and positive ANA, and elevated ESR has been reported with ACE inhibitors. Risk of pancreatitis and agranulocytosis may be increased in patients with collagen vascular disease or renal impairment.
Metabolism/Transport Effects
None known.
Drug Interactions
Alfuzosin: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk D: Consider therapy modification
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
AzaTHIOprine: ACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Risk C: Monitor therapy
CycloSPORINE: ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE (Systemic): ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk D: Consider therapy modification
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: Monitor therapy
Gold Sodium Thiomalate: ACE Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Icatibant: May diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
Iron Dextran Complex: ACE Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Risk D: Consider therapy modification
Lanthanum: May decrease the serum concentration of ACE Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: ACE Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Salicylates: May diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy. Risk C: Monitor therapy
Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Sodium Phosphates: ACE Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Telmisartan: May increase the serum concentration of Ramipril. Concentrations of the active metabolite, ramiprilat, may also be increased. Risk C: Monitor therapy
Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Thiazide Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may worsen hypertension). Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse (may have increased antihypertensive effect).
Storage
Store at controlled room temperature.
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
Dosage
Oral:
Adults:
Heart failure (unlabeled use): Initial: 1.25-2.5 mg once daily; target dose: 10 mg once daily (ACC/AHA 2009 Heart Failure Guidelines)
Hypertension: 2.5-5 mg once daily, maximum: 20 mg/day
LV dysfunction postmyocardial infarction: Initial: 2.5 mg twice daily titrated upward, if possible, to 5 mg twice daily
Reduction in risk of MI, stroke, and death from cardiovascular causes: Initial: 2.5 mg once daily for 1 week, then 5 mg once daily for the next 3 weeks, then increase as tolerated to 10 mg once daily (may be given as divided dose)
Elderly: Adjust for renal function for elderly since glomerular filtration rates are decreased; may see exaggerated hypotensive effects if renal clearance is not considered. In the management of hypertension, consider lower initial doses and titrate to response (Aronow, 2011).
Note: The dose of any concomitant diuretic should be reduced. If the diuretic cannot be discontinued, initiate therapy with 1.25 mg. After the initial dose, the patient should be monitored carefully until blood pressure has stabilized.
Dosing adjustment in renal impairment:
Clcr <40 mL/minute: Administer 25% of normal dose.
Renal failure and heart failure: Administer 1.25 mg once daily, increasing to 1.25 mg twice daily up to 2.5 mg twice daily as tolerated.
Renal failure and hypertension: Administer 1.25 mg once daily, titrated upward as possible; maximum daily dose 5 mg
Administration: Oral
Capsule is usually swallowed whole, but contents may be mixed in water, apple juice, or applesauce.
Monitoring Parameters
Blood pressure; serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential
Test Interactions
Positive Coombs' [direct]; may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent
Patient Education
Take first dose at bedtime or when sitting down (hypotension may occur). This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause increased cough (if persistent or bothersome, contact prescriber), headache, postural hypotension, dizziness, nausea, or vomiting. Immediately report swelling of face, mouth, lips, tongue or throat; chest pain or irregular heartbeat. Report respiratory difficulty or persistent cough or persistent pain in muscles, joints, or back.
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.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent. Episodes of intraoperative hypotension may be managed by fluid administration and/or modest doses of alpha-adrenergic agents. Patients who have undergone coronary artery bypass graft (CABG) surgery should have therapy reinstituted once the patient is stable or initiated in those who were not receiving ACE inhibition prior to CABG surgery; continue indefinitely (Hillis, 2011).
Cardiovascular Considerations
Heart Failure (HF): The ACC/AHA 2009 Heart Failure Guidelines recommend that ACE inhibitors be used in patients with a reduced EF (with or without HF symptoms) unless contraindicated. ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, HF. When used in patients with HF, the target dose should be achieved, if possible. Lower daily doses of ACE inhibitors have demonstrated the same mortality effects as high doses, but have not decreased hospitalizations to the extent that high-dose ACE inhibitors have, as demonstrated in the ATLAS study (Packer, 1999).
Hypertension: The ALLHAT study (ALLHAT Collaborative Group, 2002) compared CV outcomes of lisinopril, amlodipine, or chlorthalidone in hypertensive patients having at least one other risk factor for coronary heart disease. Investigators found no difference between the groups on the primary outcome of fatal coronary disease or nonfatal MI. The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors or angiotensin receptor blockers (ARBs) can be beneficial in patients with hypertension and LVH without symptoms of HF. JNC 7 suggests that patients can benefit from treatment with an ACE inhibitor if they have hypertension and HF, acute myocardial infarction, high coronary disease risk, diabetes, chronic kidney disease, or history of stroke.
Vascular Disease: The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors can be useful in preventing HF in patients who have a history of atherosclerotic vascular disease, diabetes, or hypertension with associated cardiovascular risk factors. The HOPE trial (Heart Outcomes Prevention Evaluation Study Investigators, 2000) investigated the value of an ACE inhibitor (ramipril 5-10 mg daily) versus placebo in patients who had evidence of vascular disease or diabetes (one other cardiovascular risk factor) and were at least 55 years of age. Patients were excluded if they had a low ejection fraction, HF, or were on an ACE inhibitor. The primary outcome was a composite of death from cardiovascular cause, myocardial infarction, or stroke; 9297 patients were enrolled and randomized. Ramipril significantly reduced the risk of death from CV causes, MI, or stroke over placebo. New cases of diabetes were also reduced in the ramipril group. In the EUROPA trial, patients with stable coronary artery disease (at low risk for cardiovascular events) received perindopril or placebo and were evaluated for incidence of cardiovascular events after four years of treatment. In this randomized, placebo-controlled, prospective study, 12,218 patients received either perindopril (8 mg/day, n=6110) or placebo (n=6108) and were assessed for the primary endpoint of a cardiovascular event, defined as cardiovascular death, myocardial infarction, or cardiac arrest. The study population was well balanced with respect to baseline demographics and concomitant medication use (including beta-blockers, platelet inhibitors, antihyperlipidemics, calcium channel blockers, nitrates, and diuretics). Intent-to-treat analysis revealed that 603 (10%) of placebo patients experienced the primary endpoint of a cardiovascular event compared to 488 (8%) of perindopril-receiving patients, for a 20% relative risk reduction (p=0.0003). This result was not influenced by presence of other comorbidities (eg, diabetes, hypertension) or concomitant beta-blocker, calcium channel blocker, or lipid-lowering therapies. Withdrawal from the study (postrandomization) due to adverse reactions was similar between treatment groups. Number needed to treat analysis suggests that treatment of 50 patients over a 4-year period will prevent one major cardiovascular event.
Acute Coronary Syndromes: In the treatment of unstable angina/non-ST-segment elevation MI, ACE inhibitors are recommended when hypertension persists despite treatment with nitroglycerin and a beta-blocker in patients with LV systolic dysfunction or HF and in ischemic patients with diabetes (Class I). ACE inhibitors are also recommended for all post-ACS individuals (Class IIa). According to 2004 ACC/AHA STEMI guidelines, an ACE inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion, or LVEF <0.4, in the absence of hypotension or known contraindications to this class of medicines. In the emergency management of complicated STEMI, a short-acting ACEI (eg, captopril 1-6.25 mg) may be added once the patient's systolic blood pressure is >100 mm Hg and not <30 mm Hg below baseline. The VALIANT trial evaluated the effects of valsartan (target dose: 160 mg twice daily), captopril (target dose: 50 mg twice daily), and the combination (target doses: valsartan 80 mg twice daily and captopril 150 mg once daily) in a randomized, double-blind trial of patients with acute MI (0.5-10 days post-MI) complicated by left ventricular systolic dysfunction, HF, or both. Enrollment in the study numbered 14,703 patients and followed for a median of 24.7 months. There was no difference in the primary endpoint (all cause mortality) among the 3 groups. There was no difference in incidence of CV death, recurrent MI, or hospitalization for HF either. Hypotension and renal dysfunction occurred significantly more often in the valsartan group than captopril alone. Cough, rash, and taste disturbances occurred more often in the captopril group. The authors (Pfeffer, 2003) concluded that valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after MI. Combining valsartan with captopril increased the rate of adverse events without improving survival.
Potential Adverse Events: ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. Severe hypotension may occur in patients who are sodium- and/or volume-depleted; initiate lower doses and monitor closely when starting therapy in these patients. Aging patients with a decrease in glomerular filtration (also creatinine clearance), severe HF, and renal failure may experience an exaggerated response with administration of ACE inhibitors. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, ARB therapy instituted. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.
Drug Interactions: Concomitant indomethacin therapy may blunt the reduction in sitting and 24-hour ambulatory diastolic blood pressure. Use of NSAIDs should be avoided or limited, with monitoring of blood pressure control in this setting. In patients with HF, NSAID use may be associated with an increased risk for fluid accumulation and edema.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness or drowsiness; may rarely cause nervousness, amnesia, insomnia, or depression
Mental Health: Effects on Psychiatric Treatment
May cause neutropenia; use caution with clozapine and carbamazepine; may decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels
Nursing: Physical Assessment/Monitoring
Evaluate carefully for necessary use cautions. Assess potential for interactions with other pharmacological agents or herbal products that may impact fluid balance or cardiac status. Monitor first dose carefully. Assess blood pressure and cardiac status. Monitor for cough, renal dysfunction, nausea/vomiting, hypovolemia, angioedema, and postural hypotension on a regular basis during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral: 1.25 mg, 2.5 mg, 5 mg, 10 mg
Altace®: 1.25 mg, 2.5 mg, 5 mg, 10 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Altace)
1.25 mg (30): $67.99
2.5 mg (30): $77.99
5 mg (30): $81.99
10 mg (30): $90.99
Capsules (Ramipril)
1.25 mg (100): $99.99
2.5 mg (30): $49.99
5 mg (30): $52.99
10 mg (30): $62.99
References
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, “Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),” JAMA, 2002, 288(23):2981-97.
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2012,” Diabetes Care, 2012, 35(Suppl ):11-63.
Anderson JL, Adams CD, Antman EM, et al, "2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines," Circulation, 2011, 123(18):e426-579.
Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636.
Antman EM, Hand M, Armstrong PW, et al, “2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):210-49.
Aronow WS, Fleg JL, Pepine CJ, et al, “ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents,” Circulation, 2011, 123(21):2434-506.
Chase MP, Fiarman GS, Scholz FJ, et al, “Angioedema of the Small Bowel Due to an Angiotensin-Converting Enzyme Inhibitor,” J Clin Gastroenterol, 2000, 31(3):254-7.
Chobanian AV, Bakris GL, Black HR, et al, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,” JAMA, 2003, 289(19):2560-71.
Conlin P, Moore T, Swartz S, et al, “Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients,” Hypertension, 2000, 36(3):461-5.
Cooper WO, Hernandez-Diaz S, Arbogast PG, et al, “Major Congenital Malformations After First-Trimester Exposure to ACE Inhibitors,” N Engl J Med, 2006, 354(23):2443-51.
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