| Composition |
Each capsule Restopril 2.5mg containsRamipril 2.5mg.
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| Mechanism of Action |
Ramipril and ramiprilat inhibit ACE.Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzesthe conversion of angiotensin I to the vasoconstrictor substance, angiotensinII. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensinII, which leads to decreased vasopressor activity and to decrease aldosterone secretion. The latter decrease may result in a small increaseof serum potassium.
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.RAMIPRILhas an anti hypertensive effect even in patients with low renin
hypertension.
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| Pharmacodynamics |
Single doses of Ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after dosing with approximately40%–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% 4hours after dosing, with over 80% inhibition of ACE activity remaining24 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.
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| Pharmacokinetics |
Absorption:Following oral administration of Ramipril, peak plasma concentrations of Ramipril are reached within 1 hour. The extent of absorption is atleast 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal l tract, although the rate of absorption is reduced.
Distribution:Cleavage of the ester group (primarily in the liver) converts Ramipril to its active 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%.
Metabolism: Ramipril is almost completely metabolized to Ramiprilat, which has about6 times the ACE inhibit or activity of Ramipril.
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. Less than 2%of the administered dose is recovered in urine as unchanged Ramipril.
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| INDICATIONS AND USAGE |
· Hypertension: RAMIPRILis indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.
· Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes:
RAMIPRILis indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary arterydisease, 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 micro albumin uria), to reduce the risk of myocardial infarction,stroke, or death from cardio vascular causes. RAMIPRILcan be used in addition to other needed treatment (such as antihypertensive, antiplatelet,or lipid-lowering therapy).
· Heart Failure Post-Myocardial Infarction
RAMIPRILis indicated in stable patients who have demonstrated clinicalsigns of congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of RAMIPRILto such patients has been shown to decrease the risk of death and to decrease the risks of failure-related hospitalization and progressionto severe /resistant heart failure.
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| CONTRAINDICATIONS |
RAMIPRIL is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).
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| WARNINGS & PRECAUTIONS |
Anaphylactoid and Possibly Related Reactions:
Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin ,patients receiving these drugs (including Ramipril) may be subject to adverse reactions.
Head and Neck Angioedema
Patients with a history of angioedema unrelated to ACE inhibit or 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. If angioedema of the face, tongue, or glottis occurs, discontinue treatment with Ramipril and institute appropriate therapy immediately.Administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000[0.3 mL to 0.5 mL]) promptly.
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).
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoinglow-density lipo protein apheresis with dextran sulfate absorption.
Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosteronesystem, 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 ACE inhibitors, including Ramipril, may be associated with oliguria or progressive azotemia and rarely with acute renal failure.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 RAMIPRILand/or diuretic therapy.In such patients, monitor renal function during the first few weeks of therapy. Dosage reduction of Ramipril 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.Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
Hypotension: Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depletedas a result of prolonged diuretic therapy, dietary salt restriction, dialysis,diarrhea, or vomiting. Correct volume- and salt-depletion before initiating therapy with Ramipril. If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline.
Congestive Heart Failure
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 acuterenal failure. In such patients, initiate Ramipril therapy underclose medical supervision and follow patients closely for the first 2 weeks of treatment and whenever the dose of Ramipril or diuretic is increased.
Surgery and Anesthesia
In patients under going surgery or during anesthesia with agents that produce hypotension, Ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotensionthat occurs as a result of this mechanism can be corrected by volume expansion.
Hepatic Failure and Impaired Liver Function: Rarely, ACE inhibitors, including Ramipril, have been associated with asyndrome that starts with cholestatic jaundice. Discontinue RAMIPRIL if patient develops jaundice or marked elevations of hepatic enzymes
Fetal/Neonatal Morbidity and Mortality
Angiotensin converting enzyme inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, discontinue ACE inhibitors as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible, renal failure, and death.
Dual Blockade of the Renin-Angiotensin-Aldosterone System
Patients receiving the combination of telmisartan and Ramipril did not obtain any benefit in the composite end point of cardio vascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction. Concomitant use of telmisartan and Ramipril is not recommended.
Hyperkalemia: In clinical trials with Ramipril, hyperkalemia occurred in approximately 1% of hypertensive patients receiving Ramipril. In most cases, these were isolated values, which resolved despite continued therapy.
Cough: Presumably caused by inhibition of the degradation of endogenous bradykinin, Persistent non productive cough has been reported with all ACEinhibitors, always resolving after discontinuation of therapy.
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| ADVERSE REACTIONS |
This drug may cause like other ACEIs cough, dizziness or hypotension, angioedema, anaphylactoid reactions, hematologic, gastrointestinal. The most frequent clinical side effects are :headache ,dizziness .The most common reasons for discontinuation were: cough, dizziness, and impotence.
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| 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 Ramipril. The possibility of hypotensive effects with RAMIPRILcan be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Restopril.if this is not possible ,reduce the starting dose.
RAMIPRILcan attenuate potassium loss caused by thiazide diuretics.Potassium-sparing diuretics (spironolactone, amiloride, triamterene, andothers) or potassium supplements can increase the risk of hyperkalemia.Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.
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.
Other: Neither Ramipril or its metabolites have been found to inter act with food,digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin.The co-administration of Ramipril and warfarin did not adversely affect t the anti coagulation effects of the latter drug.
Rarely, concomitant treatment with ACE inhibitors and non steroidal anti-inflammatory agents have been associated with worsening of renal failure and an increase in serum potassium.
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| PREGNANCY & LACTATION |
Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimesters).Angiotensin converting enzyme inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, discontinue ACE inhibitors as soon as possible.
Nursing Mothers: Multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use RAMIPRILin nursing mothers.
Pediatric Use:
Safety and effectiveness in pediatric patients have not been established .Irreversible kidney damage has been observed in very young rats given asingle dose of Ramipril.
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| Renal impairment |
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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 AUCO-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 sever renal function .overall, the results suggest that the starting dose of Ramipril should be adjusted down ward in patients with moderate –to- severe renal impairment.
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| DOSAGE & ADMINISTRATION |
Hypertension: The recommended initial dose for patients not receiving a diuretic is 2.5
mg once a day. Adjust dose according to blood pressure response. The usual maintenance dosage range is 2.5 mg 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, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with Ramipril alone, adiuretic can be added.
Reduction in Risk of Myocardial Infarction, Stroke, and Deathfrom Cardiovascular Causes: Initiate dosing at 2.5 mg once daily for 1 week, 5 mg once daily for the next 3 weeks, and then increase as tolerated, to a maintenance dose of10 mg once daily. If the patient is hypertensive or recently post- myocardial infraction ,RAMIPRILcan also be given as a divided dose.
Heart Failure Post-Myocardial Infarction: For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the recommended starting dose of RAMIPRIL is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.
After the initial dose ,observe the patient under medica l 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 like lihood of hypotension.the appearance of hypotension after the initial dose does not preclude subsequent careful dose titration with the drug , following effective managmement of the hypotension.
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| Dosage Adjustment |
Renal Impairment:Establish base line renal function in patients initiating Ramipril. Usual
regimens of therapy with RAMIPRILmay 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 ramprilat .
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Hypertension: For patients with hypertension and renal impairment, the recommended
initial dose is 1.25 mg RAMIPRILonce daily. Dosage may be titrated upward
until blood pressure is controlled or to a maximum total daily dose of 5 mg.
Heart Failure Post-Myocardial Infarction: For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg RAMIPRILonce daily. The dose may be increased to
1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical response and tolerability.
Volume Depletion or Renal Artery Stenosis: Blood pressure decreases associated with any dose of RAMIPRILdepend ,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, initiate dosing at1.25 mg once daily. Adjust dosage according to blood pressure response.
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| OVERDOSAGE |
Limited data on human over dosage are available. The most likely clinical manifestations would be symptom sattribut able to hypotension.Similarly, it is not known which, if any, of these substancescan be effectively removed from the body by hemodialysis.Angiotensin II could presumably serve as a specific antagonist-antidotein the setting of ramipril overdose, but angiotensin II is essentiallyunavailable 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.
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| STORAGE CONDITIONS |
Store at ( 15-30)ْC.
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| PACKAGE |
Restopril2.5mg :2 X 10 capsules packed in PVDC/Aluminum blister inside a cartoon box with a leaflet.
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