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Ramipril is an angiotensin converting enzyme (ACE) inhibitor. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°C–112°C.
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 structural formula for ramipril is:
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Its empirical formula is C23H32N2O5 and its molecular weight is 416.5 g/mol.
VOSTALLY is a clear, colorless solution for oral use that contains 1 mg/mL ramipril. The inactive ingredients are citric acid monohydrate, ethylparaben sodium, frozen peppermint flavor 5015241T, methylparaben sodium, purified water, and sucralose.
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
Ramipril 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 ramipril and placebo patients.
The most common reasons for discontinuation of ramipril were cough (1.0%), dizziness (0.5%), and impotence (0.4%). In a later 1-year study, increased cough was seen in almost 12% of ramipril 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 [see Warnings and Precautions (5.2)].
Post-Myocardial Infarction Heart Failure
AIRE Study
In AIRE, the adverse reactions occurring more commonly in ramipril than placebo and in >5% of patients taking ramipril were hypotension (11%) and cough (8%). The follow-up time was between 6 and 46 months for this study.
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril 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 Warnings and Precautions (5.5)].
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 ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.
Other Adverse Reactions
Other adverse reactions reported in controlled clinical trials (in less than 1% of ramipril patients,) or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):
Cardiovascular: palpitations
General disorders: edema, malaise, weight gain
Hematologic: bone marrow depression, agranulocytosis, neutropenia, pancytopenia hemolytic anemia, and thrombocytopenia
Gastrointestinal: pancreatitis, abdominal pain, anorexia, constipation, dry mouth, dyspepsia, dysphagia, increased salivation, and taste disturbance
Immune system: eosinophilic pneumonitis, hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), toxic epidermal necrolysis, Stevens-Johnson syndrome, an immune symptom complex which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations
Musculoskeletal and connective tissue: arthralgia, arthritis, myalgia
Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances
Respiratory, thoracic and mediastinal: dyspnea, epistaxis Reproductive system: impotence
Skin and subcutaneous tissue: erythema multiforme, hyperhidrosis, photosensitivity, purpura, onycholysis, pemphigus, pemphigoid
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during ramipril therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.
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 VOSTALLY. The possibility of hypotensive effects with VOSTALLY can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with VOSTALLY. If this is not possible, reduce the starting dose [see Dosage and Administration (2)].
Coadministration of VOSTALLY with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.
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. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on VOSTALLY and other agents that affect the RAS.
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 (including VOSTALLY) is not recommended.
Do not co-administer aliskiren with VOSTALLY in patients with diabetes. Avoid concomitant use of aliskiren with VOSTALLY in patients with renal impairment (GFR <60 mL/min/1.73 m2).
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.
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 VOSTALLY.
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.
The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. [see Warnings and Precautions (5.2)].
Included as part of the PRECAUTIONS section.
VOSTALLY can cause fetal harm when administered to a pregnant woman. 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 VOSTALLY as soon as possible [see Use in Specific Populations (8.1)].
Angioedema
Head and Neck Angioedema
Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx, including airway obstruction and some fatal reactions, have occurred in patients treated with ACE inhibitors at any time during treatment. VOSTALLY should be promptly discontinued, and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. [see Contraindications (4)]. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. Patients taking concomitant mammalian target of rapamycin (mTOR) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. [see Drug Interactions (7.7)]
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with ACE inhibitors.
These patients presented with abdominalpain (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
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 Dialysis
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
General Considerations
VOSTALLY can cause symptomatic hypotension, after the initial dose or when the dosage has been increased. Patients at risk of symptomatic hypotension include those with volume and/or salt depletion of any etiology (e.g., high dose diuretic therapy, dietary salt restriction, renal dialysis, diarrhea, or vomiting). Correct volume and/or salt depletion before initiating therapy with VOSTALLY and monitor for the first two weeks of treatment and whenever the dose of VOSTALLY and/or diuretic is increased.
If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. VOSTALLY 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 VOSTALLY. If the initial dose of 2.5 mg VOSTALLY cannot be tolerated, use an initial dose of 1.25 mg VOSTALLY to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension.
Congestive Heart Failure
In patients with congestive heart failure, with or without associated renal insufficiency, VOSTALLY may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death. In such patients, initiate VOSTALLY therapy under close medical supervision and monitor for the first 2 weeks of treatment and whenever the dose of VOSTALLY or diuretic is increased.
Surgery and Anesthesia
In patients undergoing surgery or during anesthesia with agents that produce hypotension, VOSTALLY may block angiotensin II secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
ACE inhibitors, including VOSTALLY, 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 VOSTALLY if patient develops jaundice or marked elevations of hepatic enzymes.
Worsening renal function can be caused by ACE inhibitors, including VOSTALLY, as a consequence of inhibiting the renin- angiotensin-aldosterone system in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion), treatment with ACE inhibitors, including VOSTALLY, may be associated with oliguria or progressive azotemia and rarely with acute renal failure or death. In such patients, monitor renal function during the first few weeks of therapy. Consider dose reduction, withholding, or discontinuing VOSTALLY in patients who develop a clinically significant decrease in renal function.
Drugs that inhibit the renin angiotensin system, including VOSTALLY, can cause hyperkalemia. In clinical trials with ramipril, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving ramipril. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of other drugs that raise serum potassium levels. Monitor serum potassium periodically in patients treated with VOSTALLY [see Drug Interactions (7.2)].
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.
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.
VOSTALLY is contraindicated in patients with:
VOSTALLY is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer VOSTALLY within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Drug Interactions (7.3)]
Do not co-administer VOSTALLY with aliskiren in patients with diabetes [see Drug Interactions (7.3)]
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 ramipril 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 ramipril 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 (5.8)]. 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 VOSTALLY remains to be elucidated.
While the mechanism through which VOSTALLY lowers blood pressure is believed to be primarily suppression of the renin- angiotensin-aldosterone system, VOSTALLY has an antihypertensive effect even in patients with low-renin hypertension. Although VOSTALLY 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.
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 2.5 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.
Plasma concentrations of ramipril and ramiprilat (active metabolite) increase with increase in 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. 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 ramipril, especially at low doses (2.5 mg), but the difference is not clinically significant plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase).
Following oral administration of VOSTALLY, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. Peak plasma concentrations of ramiprilat are reached 1–6 hours after drug intake. The absolute bioavailability 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.
Effect of food
The extent of absorption is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.
The serum protein binding is about 73% for ramipril and about 56% for ramiprilat; in vitro, these percentages are independent of concentration over the range of 0.01 µg/mL–10 µg/mL 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 ramipril 5 mg - 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
Metabolism
Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. 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.
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.
Specific populations
Patient with Renal Impairment
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. 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 greater than in patients with normal renal function who receive similar doses.
Patient with Hepatic Impairment
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.
Advise female patients of reproductive potential about the consequences of exposure to VOSTALLY during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible [see Use in Specific Populations (8.1)].
Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Advise patients to immediately report any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to temporarily discontinue drug until they have consulted with the prescribing physician [see Warnings and Precautions (5.2)].
Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported. Advise patients to discontinue VOSTALLY 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 VOSTALLY can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope [see Warnings and Precautions (5.3)].
Advise women not to breastfeed during treatment with VOSTALLY [see Use in Specific Populations (8.2)].
Advise patients not to use salt substitutes containing potassium without consulting their physician [see Warnings and Precautions (5.6)].
Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor to monitor for hypoglycemia closely, especially during the first month of combined use [see Drug Interactions (7.2)].
Tell patients to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign of leukopenia/neutropenia.
Instruct patients or caregivers to use an oral dosing syringe or oral dosing cup to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy.
