Control Number: 112654

Date of Preparation: October 24, 2007

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 12 DRUG INTERACTIONS 16 DOSAGE AND ADMINISTRATION 18 OVERDOSAGE 20 ACTION AND CLINICAL PHARMACOLOGY 20 STORAGE AND STABILITY 24 DOSAGE FORMS, COMPOSITION AND PACKAGING 24

PART II: SCIENTIFIC INFORMATION 26

PHARMACEUTICAL INFORMATION 26 CLINICAL TRIALS 26 DETAILED PHARMACOLOGY 27 TOXICOLOGY 29 REFERENCES 34

PART III: CONSUMER INFORMATION. 36

PrGEN-RAMIPRIL (ramipril capsules)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

GEN-RAMIPRIL is contraindicated in: Patients who are hypersensitive to this drug, to any other ACE inhibitor, or to any ingredient in the formulation. For a complete listing of ingredients see Dosage Forms, Composition and Packaging section of the product monograph. Patients who have a history of angioedema. During pregnancy In breast feeding-women In patients with haemodynamically relevant bilateral renal artery stenosis, or unilateral in the single kidney Patients with hypotensive states Concomitant use of ACE inhibitors and extracorporeal treatment leading to contact of blood with negatively charged surfaces must be avoided (see WARNINGS AND PRECAUTIONS, Immune section)

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected GEN- RAMIPRIL should be discontinued as soon as possible.

General

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of ramipril capsules, has been reported. Such possibility should be considered as part of the differential diagnosis of cough (see ADVERSE REACTIONS).

Patient alertness

Ramipril capsules may lower the state of patient alertness and/or reactivity, particularly at the start of treatment (see ADVERSE REACTIONS).

Cardiovascular

Aortic Stenosis:

There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Hypotension:

Symptomatic hypotension has occurred after administration of ramipril capsules, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, vomiting, or in other situations in which a significant activation of the rennin-angiotensin system is to be anticipated such as in patients with severe, and particularly with malignant hypertension, in patients with haemodynamically relevant left-ventricular outflow impediment (e.g., stenosis of the aortic valve) or in patients with haemodynamically relevant renal artery stenosis. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see ADVERSE REACTIONS-Clinical Trial Adverse Drug Reactions, Treatment Following Acute Myocardial Infarction- Less Common Clinical Trial Adverse Drug Reactions (<1%), Cardiovascular). Because of the potential fall in blood pressure in these patients, therapy with GEN-RAMIPRIL should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of GEN-RAMIPRIL is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has been associated with oliguria, and/or progressive azotemia, and rarely, with acute renal failure and/or death. Generally, it is recommended that dehydration, hypovalaemia or salt depletion be corrected before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed against the risk of volume overload). When these conditions have become clinically relevant, treatment with GEN-RAMIPRIL must only be started or continued if appropriate steps are taken concurrently to prevent an excessive fall in blood pressure and deterioration of renal function. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response may not be a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion in hypertensive patients. However, lower doses of GEN-RAMIPRIL and/or reduced concomitant diuretic therapy should be considered. In patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of GEN-RAMIPRIL (see ADVERSE REACTIONS-Clinical Trial Adverse Drug Reactions, Treatment Following Acute Myocardial Infarction, DOSAGE & ADMINISTRATION-Recommended Dose and Dosage Adjustment, Treatment Following Acute Myocardial Infarction).

Hematologic

Hyperkalemia and Potassium-Sparing Diuretics

Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials treated with ramipril capsules. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy in any hypertensive patient. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (see DRUG INTERACTIONS-Drug-Drug Interactions).

Neutropenia/agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Several cases of agranulocytosis, neutropenia or leukopenia have been reported in which a causal relationship to ramipril cannot be excluded. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered especially in patients with collagen vascular disease and/or renal disease (see WARNINGS AND PRECAUTIONS- Monitoring and Laboratory Tests, and ADVERSE REACTIONS- Less Common Adverse Drug reactions, Hematologic).

Hepatic/Biliary

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug. Elevations of liver enzymes and/or serum bilirubin have been reported with ramipril (see ADVERSE REACTIONS). Should the patient receiving GEN-RAMIPRIL experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigations be carried out. Discontinuation of GEN-RAMIPRIL should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. In patients with impaired liver function, response to the treatment with GEN-RAMIPRIL may be either increased or reduced. GEN-RAMIPRIL should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply (see ACTION AND CLINICAL PHARMACOLOGY - Special Populations and conditions, Hepatic Insufficiency). Rarely, ACE inhibitors, including ramipril, 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. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Immune

Angioedema - Head, and Neck

Angioedema has been reported in patients with ACE inhibitors including ramipril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, GEN-RAMIPRIL should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 to 0.5 ml of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS-Clinical Trial Adverse Drug Reactions, Essential Hypertension-Less Common Clinical Trial Adverse Drug Reactions (<1%), Body as a whole).

Angioedema - Intestinal

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 facial angioedema also occurred. The intestinal angioedema symptoms resolved after stopping the ACE inhibitor. The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients. 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). Angioedema, including laryngeal edema, may occur especially following the first dose of GEN-RAMIPRIL.

Anaphylactoid reactions during membrane exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes [e.g. polyacrylonitrile (PAN)] and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Anaphylactoid reactions during LDL apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Anaphylactoid reactions during desensitization

There have been isolated reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (e.g. bees, wasps) venoma. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Peri-Operative Considerations

Surgery/anesthesia

In patients undergoing surgery or anesthesia with agents producing hypotension, GEN- RAMIPRIL may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it may be corrected by volume repletion.

Renal

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk, therefore discontinuation of diuretic therapy may be required. Use of GEN-RAMIPRIL should include appropriate assessment of renal function. GEN-RAMIPRIL should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses (see DOSAGE AND ADMINISTRATION). Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency.

Special Populations

Pregnant Women

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, GEN-RAMIPRIL should be discontinued 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 or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy. Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

Animal Data:

No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. The doses used were: 10, 100, or 1000 mg/kg in rats (2500 times maximum human dose), 0.4, 1.0, or 2.5 mg/kg in rabbits (6.25 times maximum human dose), and 5, 50, or 500 mg/kg in cynomolgus monkeys (1250 times maximum human dose). In rats, the highest dose caused reduced food intake in the dams, with consequent reduced birth weights of the pups and weight development during the lactation period. In rabbits, maternal effects were

mortalities (high and middle dose) and reduced body weight. In monkeys, maternal effects were mortalities (high and middle dose), vomiting, and reduced weight gain.

Nursing Women

The presence of concentrations of ACE inhibitor have been reported in human milk. The use of GEN-RAMIPRIL is contraindicated during breast-feeding.

Pediatrics

The safety and effectiveness of ramipril capsules in children have not been established; therefore use in this age group is not recommended.

Geriatrics (> 65 years of age)

Although clinical experience has not identified differences in response between the elderly (>65 years) and younger patients, greater sensitivity of some older individuals cannot be ruled out (see ACTION AND CLINICAL PHARMACOLOGY-Special Populations and Conditions, Geriatrics).

Monitoring and Laboratory Tests

Hematological monitoring

Periodic monitoring of white blood cell counts should be considered to permit detection of a possible leukopenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma) or those treated with other drugs that can cause changes in the blood picture (see DRUG INTERACTIONS - Drug-Drug Interactions, Allopurinol, Immunosuppressants, Corticosteriods, Procainamide, Cytostatics and other substances that may change the blood picture).

Renal function monitoring

Use of GEN-RAMIPRIL should include appropriate assessment of renal function, particularly in the initial weeks treatment with an ACE inhibitor. Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency. Particularly careful monitoring is required in patients with:

• heart failure

• renovascular disease, including patients with haemodynamically relevant unilateral renal artery stenosis. In the latter patient group, even a small increase in serum creatinine may be indicative of unilateral loss of renal function

• impairment of renal function

• kidney transplant

Electrolyte monitoring

It is recommended that serum potassium be monitored regularly. More frequent monitoring of serum potassium is necessary in patients with impaired renal function.

Information for the Patient

Cardiovascular

Hypotension: Patients should be cautioned to report lightheadedness, especially during the first few days of GEN-RAMIPRIL therapy. If actual syncope occurs, the patients should be told to discontinue the drug and consult with their physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure, patients should be advised to consult with their physician.

Hematologic

Hyperkalemia and Potassium--Sparing Diuretics: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia/agranulocytosis: Patients should be told to report promptly to their physician any indication of infection (e.g. sore throat, fever) as this may be a sign of neutropenia (see ADVERSE REACTIONS).

Hepatic/Biliary

Patients should be advised to return to their physician if they experience any symptoms possibly related to liver dysfunction. This would include "viral-like symptoms" in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Immune

Angioedema: Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema, such as swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing. They should immediately stop taking GEN-RAMIPRIL and consult with their physician.

Special Populations

Pregnancy: Since the use of GEN-RAMIPRIL during pregnancy can cause injury and even death of the developing foetus, patients should be advised to report promptly to their physician if they become pregnant and the use of GEN-RAMIPRIL should be stopped.

DRUG INTERACTIONS

Drug-Drug Interactions

Concomitant Diuretic Therapy: WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION

Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of hypotensive effects after the first dose of ramipril capsules can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with rampril capsules. If it is not possible to discontinue the diuretic, the starting dose of ramipril capsules should be reduced and the patient should be closely observed for several hours following the initial dose and until blood pressure has stabilized (see

). Regular monitoring of serum sodium is recommended in patients undergoing concurrent diuretic therapy.

Other substances with antihypertensive potential

(e.g. nitrates): Potentiation of the antihypertensive effect is to be anticipated.

Vasopressor sympathomimetics

: These may reduce the antihypertensive effect of GEN- RAMIPRIL. Particularly close blood pressure monitoring is recommended.

Agents Increasing Serum Potassium: Non-steroidal anti-inflammatory agents

Since ramipril capsules decrease aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium, since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution. (See also

)

Agents Causing Renin Release:

The antihypertensive effect of ramipril capsules is augmented by antihypertensive agents that cause renin release (e.g. diuretics).

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 administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be further increased.

Antacids

: In one open-label, randomized, cross-over single dose study in 24 male subjects, it was determined that the bioavailability of ramipril capsules and the pharmacokinetic profile of ramiprilat were not affected by concomitant administration of the antacid, magnesium and aluminum hydroxides.

Digoxin:

In one open-label study in 12 subjects, administered multiple doses of both ramipril and digoxin, no changes were found in serum levels of ramipril, ramiprilat, and digoxin.

Warfarin:

The co-administration of ramipril capsules with warfarin did not alter the anticoagulant effects.

Acenocoumarol:

In a multi-dose double-blind, placebo-controlled, pharmacodynamic interaction study with 14 patients with mild hypertension administered both ramipril and therapeutic doses of acenocoumarol, blood pressure, thrombotest time and coagulation factors were not significantly changed.

Non-steroidal anti-inflammatory agents and acetylsalicylic acidAgents Increasing Serum Potassium

: The antihypertensive effects of ACE inhibitors may be reduced with concomitant administration of non-steroidal anti- inflammatory agents (e.g. indomethacin). Concomitant treatment of ACE inhibitors and Non- Steroidal Anti-Inflammatory drugs may lead to an increased risk of worsening of renal function and an increase in serum potassium. (See also

)

Heparin:

A rise in serum potassium concentration is possible.

Antidiabetic agents

(e.g. insulin and sulfonylurea derivates): ACE inhibitors may reduce insulin resistance. In isolated cases, such reduction may lead to hypoglycaemic reactions in patients concomitantly treated with antidiabetics. Particularly close blood glucose monitoring is, therefore, recommended in the initial phase of co-administration.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood picture

: There is an increased likelihood of haematological reactions.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Essential Hypertension

Dosage of GEN-RAMIPRIL must be individualized. Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with GEN-RAMIPRIL may need to be adjusted.

Monotherapy

The recommended initial dosage of GEN-RAMIPRIL in patients not on diuretics is 2.5 mg once daily. Dosage should be adjusted according to blood pressure response, generally, at intervals of at least two weeks. The usual dose range is 2.5 to 10 mg once daily. A daily dose of 20 mg should not be exceeded. In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not controlled with GEN-RAMIPRIL alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of GEN-RAMIPRIL.

Concomitant Diuretic Therapy

Symptomatic hypotension occasionally may occur following the initial dose of GEN-RAMIPRIL and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with GEN- RAMIPRIL to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If the diuretic cannot be discontinued, an initial dose of 1.25 mg GEN-RAMIPRIL should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of GEN-RAMIPRIL should subsequently be titrated (as described above) to the optimal response.

Use in renal impairment

For patients with a creatinine clearance below 40ml/min/1.73m2 (serum creatinine above 2.5 mg/dL), the recommended initial dose is 1.25 mg GEN-RAMIPRIL once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg. In patients with severe renal impairment (creatinine clearance below l0ml/min/1.73m2) the maximum total daily dose of 2.5 mg GEN-RAMIPRIL should not be exceeded.

Treatment Following Acute Myocardial Infarction

Dosage of GEN-RAMIPRIL must be individualized. Initiation of therapy requires consideration of concomitant medication and baseline blood pressure and should be instituted under close medical supervision, usually in a hospital, three to ten days following an acute myocardial infarction in haemodynamically stable patients with clinical signs of heart failure. The recommended initial dosage of GEN-RAMIPRIL is 2.5 mg given twice a day (b.i.d. ), one in the morning and one in the evening. If tolerated, and depending on the patient's response, dosage may be increased by doubling at intervals of one to three days. The maximum daily dose of GEN-RAMIPRIL should not exceed 5 mg twice daily (b.i.d. ). After the initial dose of GEN-RAMIPRIL, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If a patient becomes hypotensive at this dosage, it is recommended that the dosage be lowered to 1.25 mg b.i.d. following effective management of the hypotension. (see WARNINGS AND PRECAUTIONS-Cardiovascular, Hypotension). Patients who have been fluid or salt depleted, or treated with diuretics are at an increased risk of hypotension (see WARNINGS AND PRECAUTIONS-Cardiovascular, Hypotension). An excessive fall in blood pressure may occur particularly in the following: after the initial dose of GEN-RAMIPRIL; after every first increase of dose of GEN-RAMIPRIL; after the first dose of a concomitant diuretic and/or when increasing the dose of the concomitant diuretic. If appropriate, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension (see DRUG INTERACTIONS-Drug-Drug Interactions). Consideration should be given to reducing the initial dose to 1.25 mg of GEN-RAMIPRIL in these patients.

Use in renal impairment

In patients with impaired renal function (creatinine clearance of 20-50 mL/min/1.73 m2 body surface area), the initial recommended dosage is generally 1.25 mg of GEN-RAMIPRIL once daily. This dosage may be increased with caution up to 1.25 mg of GEN-RAMIPRIL twice daily, depending upon clinical response and tolerability. Insufficient data is available concerning the use of ramipril following acute myocardial infarction in patients with heart failure and severe renal failure. (see ACTION & CLINICAL PHARMACOLOGY-Pharmacokinetics, WARNINGS AND PRECAUTIONS - Renal).

Use in hepatic impairment

Insufficient data is available concerning the use of ramipril following acute myocardial infarction in patients with heart failure and hepatic dysfunction. Dose reduction and careful monitoring of these patients is required (see ACTIONS & CLINICAL PHARMACOLOGY- Pharmacokinetics, WARNINGS AND PRECAUTIONS-Hepatic/Biliary/Pancreatic).

OVERDOSAGE

Limited data are available regarding overdosage of ramipril capsules in humans. Two cases of overdosage have been reported. In the case of an overdose with ramipril, the most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by intravenous volume expansion with normal saline. Overdosage may cause excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management

Primary detoxification by, for example, gastric lavage, administration of adsorbents, sodium sulphate; (if possible during the first 30 minutes). In the event of hypotension administration of a1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution. No experience is available concerning the efficacy of forced diuresis, alteration in urine pH, haemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or haemofiltration is nevertheless considered, see also WARNINGS AND PRECAUTIONS, Immune Anaphylactoid reactions during membrane exposure section.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of essential hypertension, following acute myocardial infarction in stabilized patients with clinically confirmed heart failure. Following oral administration, ramipril is rapidly hydrolyzed to ramiprilat, its principal active metabolite. Angiotensin-converting enzyme 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 activity leads to decreased levels of angiotensin II thereby resulting in decreased vasoconstriction and decreased aldosterone secretion. The latter decrease may result in a small increase in serum potassium (see WARNINGS AND PRECAUTIONS-Hematologic, Hyperkalemia and Potassium-Sparing Diuretics). Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion result in increases in plasma renin activity. ACE is identical to kininase II. Thus, ramipril may also block the degradation of the vasodepressor peptide bradykinin, which may contribute to its therapeutic effect.

Pharmacodynamics

Administration of ramipril capsules to patients with mild to moderate essential hypertension results in a reduction of both supine and standing blood pressure usually with little or no orthostatic change or change in heart rate. Symptomatic postural hypotension is infrequent, although this may occur in patients who are salt-and/or volume-depleted (see WARNINGS AND PRECAUTIONS). In single dose studies, doses of 5-20 mg of ramipril capsules lowered blood pressure within 1-2 hours, with peak reductions achieved 3-6 hours after dosing. At recommended doses given once daily, antihypertensive effects have persisted over 24 hours. The effectiveness of ramipril capsules appears to be similar in the elderly (over 65 years of age) and younger adult patients given the same daily doses. In studies comparing the same daily dose of ramipril capsules given as a single morning dose or as a twice daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen. While the mechanism through which ramipril lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system, ramipril has an antihypertensive effect even in patients with low-renin hypertension. The antihypertensive effect of ramipril capsules and thiazide diuretics used concurrently is greater than that seen with either agent used alone. Abrupt withdrawal of ramipril capsules has not resulted in rapid increase in blood pressure.

Pharmacokinetics

Table 3: Summary of pharmacokinetic parameters of ramipril after single doses of 2.5 mg, 5 mg and 10 mg capsules

Absorption:

Following oral administration, ramipril is rapidly absorbed with peak plasma concentrations occurring within 1 hour. The extent of absorption of ramipril is 50-60% and is not significantly altered by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced. Following a single administration of up to 5 mg of ramipril, plasma concentrations of ramipril and ramiprilat increase in a manner that is greater than proportional to dose; after a single administration of 5 mg to 20 mg of ramipril the plasma concentrations for both are dose- proportional. The non-linear pharmacokinetics observed at the lower doses of ramipril can be explained by the saturable binding of ramiprilat to ACE. At steady-state, the 24-hour AUC for ramiprilat is dose-proportional over the recommended dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44% respectively when 5 mg of oral ramipril was compared to 5 mg given intravenously. Plasma concentrations of ramiprilat decline in a triphasic manner. The initial rapid decline, which represents distribution of the drug, 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 has a half-life of 9-18 hours, and the terminal elimination phase has a prolonged half-life of >50 hours. After multiple daily doses of ramipril 5-10 mg, the half-life of ramiprilat concentrations was 13-17 hours, but was considerably prolonged at 2.5 mg (27-36 hours). After once daily dosing, steady state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are higher than those seen after the first dose of ramipril capsules especially at low doses (2.5 mg).

Distribution:

Following absorption, ramipril is rapidly hydrolyzed in the liver 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 is 56%.

Metabolism:

Ramipril is almost completely metabolized to the active metabolite ramiprilat, 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 capsules, about 60% of the parent drug and its metabolites is excreted 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.

Special Populations and Conditions

Geriatrics:

A single dose pharmacokinetic study conducted in a limited number of elderly patients indicated that peak ramiprilat levels and the AUC for ramiprilat are higher in older patients (see WARNINGS AND PRECAUTIONS-Special Populations, Geriatrics).

Race:

The antihypertensive effect of angiotension converting enzyme inhibitors is generally lower in black patients than in non-blacks.

Hepatic Insufficiency:

In patients with impaired liver function, plasma ramipril levels increased about 3-fold, although peak concentrations of ramiprilat in these patients were not different from those seen in patients with normal hepatic function.

Renal Insufficiency:

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. In patients with creatinine clearance < 40 ml/min/1.73 m2, increases in Cmax and AUC of ramipril and ramiprilat compared to normal subjects were observed following multiple dosing with 5 mg ramipril (see DOSAGE AND ADMINISTRATION-Recommended Dose and Dosage Adjustment, Use in renal impairment).

STORAGE AND STABILITY

1.25 mg and 2.5 mg tablets: Store in original container at controlled room temperature 15degC to 25degC and not beyond the date indicated on the container. Protect from light. 5 mg and 10 mg tablets: Store in original container between 15degC and 30degC and not beyond the date indicated on the container. Protect from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

GEN-RAMIPRIL capsules 1.25 mg, 2.5 mg, 5 mg, and 10 mg contain the medicinal ingredient ramipril in quantities of 1.25 mg, 2.5 mg, 5 mg and 10 mg respectively. The nonmedicinal ingredients for all potencies of GEN-RAMIPRIL are: pre-gelatinized starch and hard gelatin capsules. Hard gelatin capsules for all potencies of GEN-RAMIPRIL are composed of gelatin and coloring agents specific to each potency (see below).

Capsule Printing Ink is composed of: Shellac Glaze 45% (20% Esterified) in Ethanol, Iron Oxide Black, N-Butyl Alcohol, Propylene Glycol, FD&C Blue # 2 (Indigo Carmine Aluminum Lake ) 30%-36%, FD&C Red #40/Allura Red AC Aluminum Lake (38%-42%), FD&C Blue #` Brilliant Blue FCF Aluminum (28%-31%), D&C Yellow #10 Aluminum Lake (15%-20%) or Shellac Glaze 45% (20% Esterified) in Ethanol, Iron Oxide Black, SDA 3A Alcohol 27CFR, FD&C Blue # 2 (Indigo Carmine Aluminum Lake ) 30%-36%, FD&C Red #40/Allura Red AC Aluminum Lake (38%-42%), FD&C Blue #` Brilliant Blue FCF Aluminum (28%-31%), D&C Yellow #10 Aluminum Lake (15%-20%). GEN-RAMIPRIL is available in hard gelatin capsules in the following presentations:

GEN-RAMIPRIL 1.25 mg capsules:

Hard gelatin capsule with white opaque body and yellow opaque cap. The body 'G' and the cap has 'RM1.25' both printed in black. Capsules contain a white to off-white powder.

GEN-RAMIPRIL 2.5 mg capsules:

Hard gelatin capsule with white opaque body and orange opaque cap. The body has 'G' and the cap has 'RM 2.5' both printed in black. Capsules contain a white to off-white powder.

GEN-RAMIPRIL 5 mg capsules:

Hard gelatin capsule with white body and swedish opaque cap. The body has 'G' and the cap has 'RM 5' both printed in black. Capsules contain a white to off-white powder.

GEN-RAMIPRIL 10 mg capsules:

A hard gelatin capsule with white opaque body and blue opaque cap. The body has 'G' and the cap has 'RM 10' both printed in black. Capsules contain a white to off-white powder.

GEN-RAMIPRIL capsules 1.25 mg, 2.5 mg, 5 mg and 10 mg are packaged in bottles of 100's and 500's, and cartons of 30 (2 x 15 blister-packed) capsules.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ramipril Chemical name: 2- [N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo-[3.3.0]octane-3-carboxylic acid Structural formula: Molecular formula: C23H32N2O5 Molecular mass: 416.52 Physicochemical properties: A white to off-white crystalline powder with a melting point of 105degC to 112degC. Slightly soluble in water, and freely soluble in ethanol and methanol.

CLINICAL TRIALS

Comparative Bioavailability Studies

Bioequivalence of Oral Formulation

A randomized, 2-way crossover bioequivalence study of Gen-Ramipril 5 mg capsules and Altace(r) (ramipril) 5 mg capsules was conducted in twenty-six (26/30) normal, healthy male and female subjects (age range = 18 - 55) under fasting conditions. A summary of the comparative bioavailability data is presented below.

* Gen-Ramipril (ramipril) 5 mg Capsules (Manufactured by Merck Farma y Quimica, S.A., Spain for Genpharm Inc., Canada).

+

Altace(r) (ramipril) 5 mg Capsules (manufactured by Hoechst Marion Roussel Canada Inc. [Owned by Sanofi-

Aventis Inc., Canada]), was purchased in Canada.

SS

Expressed as the arithmetic mean (CV%) only.

DETAILED PHARMACOLOGY

Table 4: Mechanism of Action

Table 5: Effects on Blood Pressure

Table 6: Pharmacokinetics and Bioavailability

TOXICOLOGY

Acute Toxicity:

Below are summarized species-specific LD50 values for both oral and intravenous administrations of ramipril.

Table 7: Acute Toxicity

The symptoms observed in mice were decreased spontaneous activity, crouching, hypothermia, dyspnea, and clonic convulsions; deaths occurred within 30 minutes after intravenous and 24 hours after oral administration. In survivors, the symptoms disappeared by 1 to 5 days after administration; necropsies revealed no abnormality in any of the surviving animals. In rats, reduced spontaneous activity was noted (oral administration), while after intravenous administration similar signs occurred as in mice; the sign of lethal toxicity was clonic convulsions (intravenous administration).

Table 8: Chronic Toxicity

Table 8: Chronic Toxicity (Continued)

Table 8: Chronic Toxicity (Continued)

Table 9: Reproduction and Teratology

Table 9: Reproduction and Teratology (Continued)

Mutagenicity:

Ramipril was not mutagenic in the Ames microbial mutagen test, the HGPRT test in V79 cells, the micronucleus test in mice and the UDS test in human A549 cells.

Carcinogenicity:

There was no evidence of a carcinogenic effect when ramipril was administered for 104 weeks to NMRI mice at doses up to 1000 mg/kg/day and to Wistar rats at doses up to 500 mg/kg/day.

REFERENCES

1. Benetos A, Vasmant D, Thiery P, et al. Effects of Ramipril on Arterial Hemodynamics. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S153-S15

2. Burris JF. The Effect of Ramipril on Ambulatory Blood Pressure: A Multicenter Trial. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S131-S133

3. Carre A, Vasmant D, Elmalem J, et al. Tolerability of Ramipril in a Multicenter Study of Mild-to-Moderate Hypertension in General Practice. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S141-S143.

4. Hall AS, Winter C, Bogle SM, Mackintosh AF, Murray GD, Ball SG, on behalf of the AIRE Study Investigators: The Acute Ramipril Efficacy (AIRE) study: rationale, design, organization and outcome definitions. J Cardiovasc Pharmacol 1991, 18(Suppl.2): S105-S 109.

5. Heidbreder K, Froer K-L, Bauer B et al. Efficacy and Safety of Ramipril in Combination with Hydrochlorothiazide: Results of a Long-Term Study. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S169-S173.

6. Hosie J and Meredith P. The Pharmacokinetics of Ramipril in a Group of Ten Elderly Patients with Essential Hypertension. J of Cardiovascular Pharmacology 1991, 18(Suppl 2):S125-S127.

7. Lenox-Smith AJ, Street RB and Kendall FD. Comparison of Ramipril Against Atenolol in Controlling Mild-to-Moderate Hypertension. J of Cardiovascular Pharmacology 1991, 18(Suppl.2): S150-S152.

8. Manhem PJO, Ball SG, Morton JJ, Murray GD, Leckie BJ, Fraser R, Robertson JIS. A dose- response study of Hoe 498, a new non-sulphydryl converting enzyme inhibitor, on blood pressure, pulse rate and the renin-angiotensin-aldosterone system in normal man. Br J Clin Pharmacol 1985, 20: 27-35.

9. McCarron D and The Ramipril Multicenter Study Group. 24-Hour Blood Pressure Profiles in Hypertensive Patients Administered Ramipril or Placebo Once Daily: Magnitude and Duration of Antihypertensive Effects. Clin Cardiol 1991, 14: 737-742.

10. Mills TP. Ramipril: A review of the new ACE inhibitor. J of the Arkansas Medical Society, February 1992, 88 (9): 437-440

11. Reinich W, Hoffmann H, Hoffmann W. Treatment of hypertension with the new ACEinhibitor Ramipril. (Translation) Therapiewoche Osterreich 1992, 7: 112-119.

12. Rosenthal J, Buehler G, Koenig W, et al. Effect of Angiotensin-Converting Enzyme Inhibition on Human Tissue Renin. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S122-S124.

13. Saalbach R, Wochnik G, Mauersberger H, et al. Antihypertensive Efficacy, Tolerance, and Safety of Ramipril in Young vs. Old Patients: A Retrospective Study. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S134-S136.

14. Schnaper HW. Dose-Response Relationship of Ramipril in Patients with Mild-to-Moderate Hypertension. J of Cardiovascular Pharmacology 1991, 18(Suppl. 2): S128-S130.

15. Schreiner M, Berendes B, Verho M, et al. Antihypertensive Efficacy, Tolerance, and Safety of Long-Term Treatment with Ramipril in Patients with Mild-to-Moderate Essential Hypertension. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S137-S140.

16. Vasmant D, Lendresse P, Lemarie J-C, et al. Comparison of Response Rates to the Angiotensin-Converting Enzyme Inhibitor Ramipril in Mild-to-Moderate Hypertension in a Double-Blind, Parallel-Group Study and an Open Single-Blind Study. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S144-S146.

17. Vierhapper H, Witte U, Waldhausl W. Unchanged pressor effect of norepinephrine in normal man following the oral administration of two angiotensin converting enzyme inhibitors, captopril and Hoe 498. J Hypertens 1986, 4: 9-11.

18. The Acute Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993, 342: 821-828.

19. Altace(r) Product Monograph: Sanofi-Aventis Canada Inc., Submission Control No.114245, Date of Revision: August 22, 2007.