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Restopril 10 ( Ramipril )

  • Effective Material
    Ramipril 10mg
  • Caliber
    10 mg
  • Pharmacologic Form
  • Therapeutic Categories
    Cardiovascular Drugs
  • Pharmaceutical Form
Each capsule Restopril 10mg containsRamipril 10mg.
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

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.
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.

·         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.
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).
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.
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.

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.
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.
Renal impairment

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.
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.
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 .


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.
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.
Store at ( 15-30)ْC.
Restopril10mg :2 X 10 capsules packed in PVDC/Aluminum blister inside a cartoon box with a leaflet.