Ramipril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. 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.

 

Following oral administration of Ramipril, peak plasma concentrations of Ramipril are reached within one hour. The extent of absorption is at least 50 – 60% and is not significantly influenced by the presence of food in the GI tract, although the rate of absorption is reduced. 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%. After oral administration of Ramipril, about 60% of the parent drug and its metabolites is eliminated in the urine, and about 40% is found in the feces.  

 

Ramipril is indicated in patients 55 years older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes .

- Hypertension: Ramipril is indicated  for the treatment of  hypertension. It may be used alone or in combination with thiazide diuretics. In considering use of Ramipril, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-black.

- Heart failure post myocardial infarction: Ramipril is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of Ramipril to such patients has been shown to decrease the risk of death and to decrease the risk of failure – related hospitalization and progression to severe/resistant heart failure.

 

Ramipril is contraindicated in patients who are hypersensitive to this product or any other angiotensin converting enzyme inhibitors (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. 

 

Anaphylactoid and possibly related reactions: Patients receiving ACE inhibitors (including Ramipril) may be subject to a variety of adverse reactions, some of them serious. 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.

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 angiotensin converting enzyme inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Ramipril should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1,000 (0.3 ml to 0.5 ml) should be promptly administered.

Intestinal angioedema: Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (with or without nausea or vomiting).

Hypotension: Ramiapril can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, Ramipril 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. Volume and/or salt depletion should be corrected before initiating therapy with Ramipril. In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure or death. In such patients, Ramipril therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of Ramipril or diuretic is increased. If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of physiological saline. Ramipril treatment usually can be continued following restoration of blood pressure and volume.

Hepatic failure: Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Neutropenia/agranulocytosis: 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. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

Care must be taken during desensitization treatment with hymenoptera venom of patients receiving ACE inhibitors due to the possibility life-threatening anaphylactoid reactions.

 

Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including Ramipril, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of Ramipril and/or diuretic therapy. In such patients renal function should be monitored 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 Ramipril has been given concomitantly with a diuretic. Dosage reduction of Ramipril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function.

Hyperkalemia: Risk factors for the development of hyperkalemia include impaired renal function, 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 Ramipril.

Impaired liver function: Since 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 since the renin-angiotensin system may be activated in patients with severe liver cirrhosis and/or ascites. Particular caution should be exercised in treating these patients.

Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/anesthesia: Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

 

Pregnancy: Female patients of childbearing age should be asked to report pregnancies to their physicians as soon as possible.

Angioedema: Angioedema including laryngeal edema can occur with treatment with ACE inhibitors especially following the first dose. Patients should be so advised and told 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.

Symptomatic hypotension: Patients should be cautioned that light headedness can occur especially during the first days of therapy, and it should be reported patients should be told that if syncope occurs Ramipril should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake or excessive perspiration diarrhea or vomiting can lead to an excessive fall in blood pressure with the same consequences of lightheadedness and possible syncope.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Neutropenia: Patients should be told to promptly report any indication of infection (sore throat, fever) which could be sign of neutropenia.

 

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 Ramipril.

With nonsteroidal anti-inflammatory agents: Rarely, concomitant treatment with ACE inhibitors and nonsteroidal anti-inflammatory agents have been associated with worsening of renal failure and an increase in serum potassium.

With 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 Ramipril. The possibility of hypotensive effects with Ramipril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Ramipril. If this is not possible, the starting dose should be reduced.

With potassium supplements and potassium-sparing diuretics: Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.

With lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Other: Neither Ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of Ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of Ramipril and warfarin did not adversely affect the anticoagulant effects of the latter drug. Additionally, co-administration of Ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects’ state of anti-coagulation.

 

Pregnancy categories: C (first trimester) and D (second and third trimesters). Pregnancy must be excluded before starting treatment and must be avoided, otherwise there is a risk of harm to the fetus. When pregnancy is detected, Ramipril should be discontinued as soon as possible for nursing mothers because multiple doses may produce low milk concentrations that are not predictable from single doses. Women receiving Ramipril should not breast feed.

 

No overall difference in effectiveness or safety were observed between these patients 75 old and younger patients.

 

Safety and effectiveness in pediatric patients have not been established.

 

Including: Dizziness, light – headedness, fatigue, nausea, vomiting, diarrhea, dry cough or blurred vision, fainting, decreased sexual ability, fever and liver problems.

 

Blood pressure decreases associated with any dose of Ramipril depend in part, on the presence or absence of volume depletion (e.g. past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, the initial starting dose should be 1.25 mg once daily.

Reduction in risk of myocardial infarction, stroke and death from cardiovascular causes: Ramipril should be given at an initial dose of 2.5 mg once a day for 1 week, then 5mg once a day for the next 3 weeks, and then increased as tolerated, to a maintenance dose of 10 mg once a day. If the patients is hypertensive or recently post myocardial infarction, it can also be given as a divided dose.

Hypertension: The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Dosage should be adjusted according to the blood pressure response. The usual maintenance dosage range is 2.5 to 20 mg per day administered as a single dose or in two equally divided doses. In some patients treated once daily the antihypertensive effect may diminish toward the end of the dosing interval in such patients an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with Ramipril alone, a diuretic can be added.

Heart failure post myocardail infraction: For the treatment of post infraction patients who have shown signs of congestive failure, the recommended starting dose of Ramipril is 2.5 mg twice daily (5mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily, and after one week at the starting dose. Patients should then be titrated (if tolerated) toward a target dose of 5 mg twice daily with dosage increases being about 3 weeks apart. After the initial dose of Ramipril the patients should be observed under medical supervision for at least two hours until blood pressure has stabilized and for at least an additional hour. If possible the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension Ramipril capsule is usually swallowed whole. Ramipril capsule can also be opened and the contents sprinkled water or apple juice. To be sure that Ramipril is not lost when such a mixture is used the mixture should be consumed in its entirety. Concomitant administration of Ramipril with potassium supplements, potassium salt substitutes, or potassium - sparing diuretic can lead to increases of serum potassium. In patients who are currently being treated with diuretic, symptomatic hypotension occasionally can occur following the initial dose of Ramipril. To reduce the likelihood of hypotension, the diuretic should if possible be discontinued 2 to 3 days prior to beginning therapy with Ramipril. Then if blood pressure is not controlled with Ramipril alone, diuretic therapy should be resumed. If the diuretic cannot discontinued, an initial dose of 1.25 mg Ramipril should be used to avoid excess hypotension.

In patients with creatinine clearance <40 ml/min/1073 m² doses only 25% of those normally used should be expected to induce full therapeutic levels of Ramipril.

Hypertension: For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg once daily. Dosage may be titrated upward until blood pressure is controlled or to maximum total daily dose of 5 mg.

Heart failure post myocardail infarction: Patients with heart failure and renal impairment the recommended initial dose is 1.25 mg once daily. The dose may increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

 

RAMIPRIL ELSaad 1.25 – Capsules: A pack of 10 capsules. Each capsule contains 1.25 mg Ramipril.

RAMIPRIL ELSaad 2.5 – Capsules: A pack of 10 capsules. Each capsule contains 2.5 mg Ramipril.

RAMIPRIL ELSaad 5 – Capsules: A pack of 10 capsules. Each capsule contains 5 mg Ramipril.

RAMIPRIL ELSaad 10 – Capsules: A pack of 10 capsules. Each capsule contains 10 mg Ramipril.

 

Store RAMIPRIL ELSaad  – Capsules at temperature between (15-30)°C.