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Product Name
Chemical Name
Therapeutic Category
Cardiovascular drugs
Pharmacologic Category
Angiotensin-Converting Enzyme (ACE) Inhibitor
Pharmaceutical Form
Ramipril 1.25mg /2.5mg /5mg /10mg
Monitoring Parameters
Dosing: Adult
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: Oral: 2.5-5 mg once daily, maximum: 20 mg/day
LV dysfunction postmyocardial infarction: Oral: Initial: 2.5 mg twice daily titrated upward, if possible, to 5 mg twice daily
To reduce the 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 10 mg once daily (may be given as divided dose)
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: Geriatric

Refer to adult dosing. 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).

Dosing: 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.
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/Investigational
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
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% (Limited to important or life-threatening): Agitation, agranulocytosis, amnesia, anaphylactoid reaction, angioedema, arrhythmia, bone marrow depression, convulsions, depression, dysphagia, dyspnea, edema, eosinophilia, erythema multiforme, hearing loss, hemolytic anemia, hepatitis, hypersensitivity reactions (urticaria, rash, fever), impotence, insomnia, myalgia, MI, neuropathy, onycholysis, pancreatitis, pancytopenia, paresthesia, pemphigoid, pemphigus, photosensitivity, proteinuria, somnolence, Stevens-Johnson syndrome, symptomatic hypotension, thrombocytopenia, toxic epidermal necrolysis
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/or agranulocytosis may be increased in patients with collagen vascular disease or renal impairment.
Warnings / Precautions Drug
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]: Based on human data, ACEIs can cause injury and death to the developing fetus when used in the second and third trimesters. ACEIs should be discontinued 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.
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
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
Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
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
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
Telmisartan: May increase the serum concentration of Ramipril. Concentrations of the active metabolite, ramiprilat, may also be increased. 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
C (1st trimester); D (2nd and 3rd trimesters)
Pregnancy Implications
Due to adverse events observed in some animal studies, ramipril is considered pregnancy category C during the first trimester. Based on human data, ramipril is considered pregnancy category D if used during the second and third trimesters (per the manufacturer; however, one study suggests that fetal injury may occur at anytime during pregnancy). Ramipril crosses the placenta. First trimester exposure to ACE inhibitors may cause major congenital malformations. An increased risk of cardiovascular and/or central nervous system malformations was observed in one study; however, an increased risk of teratogenic events was not observed in other studies. Second and third trimester use of an ACE inhibitor is associated with oligohydramnios. Oligohydramnios due to decreased fetal renal function may lead to fetal limb contractures, craniofacial deformation, and hypoplastic lung development. The use of ACE inhibitors during the second and third trimesters is also associated with anuria, hypotension, renal failure (reversible or irreversible), 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. Those 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, especially during the second and third trimester, should be monitored for hyperkalemia, hypotension, and oliguria.
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.
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
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