Ramipril

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Ramipril
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2], Amr Marawan, M.D. [3]

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Black Box Warning

FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
  • When pregnancy is detected, discontinue Altace as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Overview

Ramipril is an Angiotensin converting enzyme inhibitor that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, asthenia, dizziness, headache, cough and fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension
  • Dosing Information (not receiving diuretic)
  • Initial dose : Ramipril 2.5 mg PO qd should be used.Adjust dose according to blood pressure response.
  • Maintenance dose: Ramipril 2.5-20 mg PO qd or bid
  • In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with ALTACE alone, a diuretic can be added.
  • Reduction in Myocardial Infarction, Stroke ,and Death from Cardiovascular Causes
  • Dosage for 1st week: 2.5 mg PO qd
  • Dosage for the next 3 weeks: 5 mg PO qd
  • Maintaining dosage: 10 mg PO qd (if tolerated)
  • If the patient is hypertensive or recently post-myocardial infarction, ALTACE can also be given as a divided dose.
Heart failure in Post-Myocardial Infarction Patients
  • Dosing Information
  • Initial dose for the 1st week : 2.5 mg PO bid
  • For patients become hypotensive: switched to 1.25 mg PO bid
  • Dosage from the 2nd dosage: 5 mg PO bid, with dosage increases being about 3 weeks apart.
  • After the initial dose of ALTACE, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension (see Warnings and Precautions, Drug Interactions).
Dosage Adjustment
  • Indication for adjustment: In patients with estimated creatinine clearance ≤40 mL/min. (Usual dosage maybe safe in patients with creatinine clearance >40 mL/min )
  • Adjustmented dosage: 25% of the usual dose is expected to produce full therapeutic levels.
  • Indication for adjustment: For patients with hypertension and renal impairment.
  • Adjusted dosage: 1.25 mg PO bid, max: 2.5 mg PO bid (depending on clinical response and tolerability).
  • Initiate dosage: 1.25 mg PO qd. Adjust dosage according to blood pressure response.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Heart Failure

  • Dosing Information/Recommendation
  • Initial dosage: 2.5 mg PO bid
  • Maintaining dosage: 5 mg PO bid (if tolerated)

Non–Guideline-Supported Use

Cardiac syndrome X
Diabetic nephropathy
  • Dosing information
  • 10 mg/day [1]
  • 5 mg/day or more [2]
  • 1.25 mg/day[3]
Erythrocytosis - Transplant of kidney
  • Dosing information
Essential hypertension - Left ventricular hypertrophy
  • Dosing information
Nondiabetic kidney disease
  • Dosing information
Prophylaxis treatment of recurrent atrial fibrillation
  • Dosing information
Mitral valve regurgitation
  • Dosing information

Peripheral arterial occlusive disease=

  • Dosing information
Renovascular hypertension
  • Dosing information

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

safety and efficacy not established in pediatric patients

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information about guideline-supported off-label use

Non–Guideline-Supported Use

  • There is limited information about Off-Label Non–Guideline-Supported Use of Ramipril tablet in pediatric patients.

Contraindications

Warnings

FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
  • When pregnancy is detected, discontinue Altace as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Anaphylactoid and Possibly Related Reactions

Angioedema

Head and Neck Angioedema
  • Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
  • Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Altace and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly.
  • In considering the use of Altace, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients.
  • In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different statistically.
Intestinal Angioedema
  • Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions During Desensitization

  • Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure

  • Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hepatic Failure and Impaired Liver Function

  • Rarely, ACE inhibitors, including Altace, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue Altace if patient develops jaundice or marked elevations of hepatic enzymes.
  • As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.

Renal Impairment

  • In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon discontinuation of Altace and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Altace has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Altace and/or discontinuation of the diuretic may be required.

Neutropenia and Agranulocytosis

  • In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

Hypotension

General Considerations

  • Altace can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, Altace, has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume- and salt-depletion before initiating therapy with Altace.
  • If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. Altace treatment usually can be continued following restoration of blood pressure and volume.

Heart Failure Post-Myocardial Infarction

  • In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Altace. If the initial dose of 2.5 mg Altace cannot be tolerated, use an initial dose of 1.25 mg Altace to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension.

Congestive Heart Failure

Surgery and Anesthesia

  • In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Fetal Toxicity

Pregnancy Category D

Dual Blockade of the Renin-Angiotensin-Aldosterone System

  • Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Altace and other agents that affect the RAS.

Telmisartan

  • The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.

Aliskiren

  • Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment (GFR <60 mL/min/1.73 m2). (see Drug Interactions)

Hyperkalemia

  • In clinical trials with Altace, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving Altace. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Altace.

Cough

  • Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin converting enzyme inhibitor induced-cough in the differential diagnosis of cough.

Adverse Reactions

Clinical Trials Experience

  • Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypertension

  • Altace has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in Altace and placebo patients.
  • The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving Altace in placebo-controlled trials were headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in Altace patients than in patients given placebo. Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with Altace. The most common reasons for discontinuation were cough (1.0%), dizziness (0.5%), and impotence (0.4%).
  • Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% vs. 1%, respectively).
  • In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the Altace group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of Altace patients, with about 4% of patients requiring discontinuation of treatment.

Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

HOPE Study
  • Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials.
This image is provided by the National Library of Medicine.

Heart Failure Post-Myocardial Infarction

AIRE Study
  • Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on Altace are shown below. The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study.
This image is provided by the National Library of Medicine.

Other Adverse Reactions

  • Other adverse reactions reported in controlled clinical trials (in less than 1% of Altace patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain)

Body as a whole

Cardiovascular

Hematologic

  • Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving Altace alone and in 1.5% of patients receiving Altace plus a diuretic.

Renal

Angioneurotic edema

Gastrointestinal

Dermatologic

Neurologic and Psychiatric

Miscellaneous

Diuretics

  • Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose.

Other Antihypertensive Agents

  • The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
  • In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended.

Lithium

  • Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Gold

  • Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Altace.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

  • In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy.

Aliskiren

  • Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment (GFR <60 mL/min/1.73 m2).

mTOR Inhibitors

Carcinogenesis, Mutagenesis, Impairment of Fertility

  • No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
  • No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

Other

  • Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during ALTACE therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.

Clinical Laboratory Test Findings

Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE alone, and in 1.5% of patients receiving ALTACE and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ALTACE alone and in 3% of patients receiving ALTACE with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see Drug Interactions). As ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient's serum potassium frequently (see Drug Interactions).

Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving ALTACE plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.

Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with ALTACE administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

Drug Interactions

Diuretics

  • Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose.

Other Antihypertensive Agents

  • The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
  • In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended.

Lithium

  • Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Gold

  • Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Altace.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

  • In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy.

Aliskiren

  • Do not co-administer aliskiren with Altace in patients with diabetes. Avoid concomitant use of aliskiren with Altace in patients with renal impairment.

mTOR Inhibitors

  • Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.

Carcinogenesis, Mutagenesis, Impairment of Fertility

  • No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.
  • No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

Other

  • Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Altace as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
  • In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Altace unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Altace for hypotension, oliguria, and hyperkalemia.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramipril in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Ramipril during labor and delivery.

Nursing Mothers

  • Ingestion of a single 10 mg oral dose of Altace resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use Altace in nursing mothers.

Pediatric Use

  • Safety and efficacy not established in pediatric patients

Geriatic Use

  • Of the total number of patients who received Altace in U.S. clinical studies of Altace, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
  • One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.

Gender

There is no FDA guidance on the use of Ramipril with respect to specific gender populations.

Race

There is no FDA guidance on the use of Ramipril with respect to specific racial populations.

Renal Impairment

  • Establish baseline renal function in patients initiating Altace. Usual regimens of therapy with Altace may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25% of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat.
  • A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of creatinine clearance: normal (>80 mL/min), mild impairment (40–80 mL/min), moderate impairment (15–40 mL/min), and severe impairment (<15 mL/min). On average, the AUC0–24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted downward in patients with moderate-to-severe renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Ramipril in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Ramipril in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Ramipril in patients who are immunocompromised.

Administration and Monitoring

Administration

  • General Dosing Information
  • Generally, swallow ALTACE capsules whole. The ALTACE capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.

Concomitant administration of ALTACE with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see Warnings and Precautions).

Monitoring

FDA Package Insert for Ramipril contains no information regarding Monitoring.

IV Compatibility

FDA Package Insert for Ramipril contains no information regarding IV Compatibility.

Overdosage

Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.

Pharmacology

Ramipril description 01.jpg
Ramipril
Systematic (IUPAC) name
(2S,3aS,6aS)-1-[(2S)-2-[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]aminopropanoyl]-octahydrocyclopenta[b]pyrrole-2-carboxylic acid
Identifiers
CAS number 87333-19-5
ATC code C09AA05
PubChem 5362129
DrugBank DB00178
Chemical data
Formula C23H32N2O5 
Mol. mass 416.511 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 28%
Protein binding 73% (ramipril)
56% (ramiprilat)
Metabolism Hepatic, to ramiprilat
Half life 2 to 4 hours
Excretion Renal (60%) and fecal (40%)
Therapeutic considerations
Pregnancy cat.

D

Legal status

POM(UK) -only(US)

Routes Oral

Mechanism of Action

  • Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Altace alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with Altace and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater (see Warnings and Precautions). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
  • The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.
  • Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of Altace remains to be elucidated.
  • While the mechanism through which Altace lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Altace has an antihypertensive effect even in patients with low-renin hypertension. Although Altace was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients.

Structure

Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C. The CAS Registry Number is 87333-19-5. Ramipril's chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester. The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.

The structural formula for ramipril is:

This image is provided by the National Library of Medicine.

Its empirical formula is C23H32N2O5 and its molecular weight is 416.5. Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group.

Pharmacodynamics

  • Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.

Pharmacokinetics

Absorption
  • Following oral administration of Altace, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.
  • In a trial in which subjects received Altace capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the concomitant liquid or food.
Distribution
  • Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 µg/mL–10 µg/mL.
Metabolism
  • Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive.
  • Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg–20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.
  • After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of Altace, especially at low doses (2.5 mg), but the difference is clinically insignificant.
  • Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of Altace 5 mg–10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
  • In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
  • In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.
Excretion
  • After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.
  • The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility. No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

Clinical Studies

Hypertension

  • Administration of Altace to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. Use of Altace in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.
  • In single-dose studies, doses of 5 mg–20 mg of Altace lowered blood pressure within 1–2 hours, with peak reductions achieved 3–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4–12 weeks) controlled studies, once-daily doses of 2.5 mg–10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50–60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive effect with once-daily dosing is not adequately maintained.
  • In most trials, the antihypertensive effect of Altace increased during the first several weeks of repeated measurements. The antihypertensive effect of Altace has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of Altace has not resulted in a rapid increase in blood pressure. Altace has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. Altace was approximately as effective as other ACE inhibitors and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril.
  • Altace was less effective in blacks than in Caucasians. The effectiveness of Altace was not influenced by age, sex, or weight.
  • In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.

Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

  • The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial design study conducted in 9541 patients (4645 on Altace) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of Altace (10 mg orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.
  • The HOPE study results showed that Altace (10 mg/day) significantly reduced the rate of myocardial infarction, stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint. The relative risk of the composite outcomes in the Altace group as compared to the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 year of treatment.
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This image is provided by the National Library of Medicine.
  • Altace was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not Altace was equally effective in ethnic subgroups.
  • This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of Altace on the combined endpoint and its components were similar in diabetics (N=3577) to those in the overall study population.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
  • Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.

Heart Failure Post-Myocardial Infarction

  • Altace was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing Altace to placebo in stable patients, 2–9 days after an acute myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days.
  • Patients randomized to Altace treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to Altace) of 5 mg twice daily. Patients were then followed for an average of 15 months, with the range of follow-up between 6 and 46 months.
  • The use of Altace was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of Altace therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).

How Supplied

Altace is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules.

Storage

Store at controlled room temperature (59°–86°F).

Images

Drug Images

Ramipril 1.25 mg NDC 61570-110-01.jpg

Drug Name: Ramipril
Ingredient(s): starch, corn, gelatin, titanium dioxide, fd&c blue no. 1
Imprint: Altace;1;25;mg;MP
Dosage: 1.25 mg
Color(s): Yellow
Shape: Capsule
Size (mm):
Score: 1
NDC:61570-110-01

Drug Label Author: Pfizer Laboratories Div Pfizer Inc

This pill image is provided by the National Library of Medicine's PillBox.
Ramipril 10 mg NDC 61570-120-01.jpg

Drug Name: Ramipril
Ingredient(s): starch, corn, gelatin, titanium dioxide, fd&c blue no. 1
Imprint: Altace;10;mg;MP
Dosage: 10 mg
Color(s): Blue
Shape: Capsule
Size (mm):
Score: 1
NDC:61570-120-01

Drug Label Author: Pfizer Laboratories Div Pfizer Inc

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Ramipril 2.5 mg NDC 61570-111-01.jpg

Drug Name: Ramipril
Ingredient(s): starch, corn, gelatin, titanium dioxide, fd&c blue no. 1
Imprint: Altace;2;5;mg;MP
Dosage: 2.5 mg
Color(s): Orange
Shape: Capsule
Size (mm):
Score: 1
NDC:61570-111-01

Drug Label Author: Pfizer Laboratories Div Pfizer Inc

This pill image is provided by the National Library of Medicine's PillBox.
Ramipril 5 mg NDC 61570-112-01.jpg

Drug Name: Ramipril
Ingredient(s): starch, corn, gelatin, titanium dioxide, fd&c blue no. 1
Imprint: Altace;5;mg;MP
Dosage: 5 mg
Color(s): Red
Shape: Capsule
Size (mm):
Score: 1
NDC:61570-112-01

Drug Label Author: Pfizer Laboratories Div Pfizer Inc

This pill image is provided by the National Library of Medicine's PillBox.

Package and Label Display Panel

Ramipril label-01.jpg
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Ramipril label-02.jpg
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Patient Counseling Information

  • Angioedema
  • Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
  • Neutropenia
  • Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.
  • Symptomatic Hypotension
  • Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported. Advise patients to discontinue ALTACE if syncope (fainting) occurs, and to follow up with their health care providers.

Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ALTACE can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

  • Pregnancy
  • Female patients of childbearing age should be told about the consequences of exposure to Altace during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
  • Hyperkalemia
  • Advise patients not to use salt substitutes containing potassium without consulting their physician.

Precautions with Alcohol

Alcohol-Ramipril tablet interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Ramipril Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Ramipril Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. 1.0 1.1 1.2 Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J et al. (2008) Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 372 (9638):547-53. DOI:10.1016/S0140-6736(08)61236-2 PMID: 18707986
  2. Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ (1999) Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Collaborative Study Group. Am J Kidney Dis 34 (5):809-17. PMID: 10561135
  3. Marre M, Lievre M, Chatellier G, Mann JF, Passa P, Ménard J et al. (2004) Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 328 (7438):495. DOI:10.1136/bmj.37970.629537.0D PMID: 14960504
  4. Esposito R, Giammarino A, De Blasio A, Martinelli V, Cirillo F, Scopacasa F et al. (2007) Ramipril in post-renal transplant erythrocytosis. J Nephrol 20 (1):57-62. PMID: 17347974
  5. Grandi AM, Solbiati F, Laurita E, Maresca AM, Nicolini E, Marchesi C et al. (2008) Effects of dual blockade of Renin-Angiotensin system on concentric left ventricular hypertrophy in essential hypertension: a randomized, controlled pilot study. Am J Hypertens 21 (2):231-7. DOI:10.1038/ajh.2007.47 PMID: 18174880
  6. Eichstaedt H, Danne O, Langer M, Cordes M, Schubert C, Felix R et al. (1989) Regression of left ventricular hypertrophy under ramipril treatment investigated by nuclear magnetic resonance imaging. J Cardiovasc Pharmacol 13 Suppl 3 ():S75-80. PMID: 2474110
  7. Lièvre M, Guéret P, Gayet C, Roudaut R, Haugh MC, Delair S et al. (1995) Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. HYCAR Study Group. Hypertension 25 (1):92-7. PMID: 7843761
  8. Nielsen FS, Sato A, Ali S, Tarnow L, Smidt UM, Kastrup J et al. (1998) Beneficial impact of ramipril on left ventricular hypertrophy in normotensive nonalbuminuric NIDDM patients. Diabetes Care 21 (5):804-9. PMID: 9589245
  9. Kindler J, Schunkert H, Gassmann M, Lahn W, Irmisch R, Debusmann ER et al. (1989) Therapeutic efficacy and tolerance of ramipril in hypertensive patients with renal failure. J Cardiovasc Pharmacol 13 Suppl 3 ():S55-8. PMID: 2474105
  10. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G (1998) Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy. Lancet 352 (9136):1252-6. PMID: 9788454
  11. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M et al. (1999) Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 354 (9176):359-64. DOI:10.1016/S0140-6736(98)10363-X PMID: 10437863
  12. Belluzzi F, Sernesi L, Preti P, Salinaro F, Fonte ML, Perlini S (2009) Prevention of recurrent lone atrial fibrillation by the angiotensin-II converting enzyme inhibitor ramipril in normotensive patients. J Am Coll Cardiol 53 (1):24-9. DOI:10.1016/j.jacc.2008.08.071 PMID: 19118720
  13. Høst U, Kelbaek H, Hildebrandt P, Skagen K, Aldershvile J (1997) Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 80 (5):655-8. PMID: 9295005
  14. Ahimastos AA, Lawler A, Reid CM, Blombery PA, Kingwell BA (2006) Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial. Ann Intern Med 144 (9):660-4. PMID: 16670135
  15. Tillman DM, Adams FG, Gillen G, Morton JJ, Robertson JI (1987) Ramipril for hypertension secondary to renal artery stenosis. Changes in blood pressure, the renin-angiotensin system and total and divided renal function. Am J Cardiol 59 (10):133D-142D. PMID: 3034022
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"mm" can not be assigned to a declared number type with value 14.
"mm" can not be assigned to a declared number type with value 14.
"mm" can not be assigned to a declared number type with value 14.

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