PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 10 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 17 DOSAGE FORMS, COMPOSITION AND PACKAGING 17

PART II: SCIENTIFIC INFORMATION 19

PHARMACEUTICAL INFORMATION 19 CLINICAL TRIALS 20 DETAILED PHARMACOLOGY 23 TOXICOLOGY 25 REFERENCES 30

PART III: CONSUMER INFORMATION 32

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NOVO-RAMIPRIL

(ramipril)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

NOVO-RAMIPRIL is contraindicated in:

• Patients who are hypersensitive to this drug, to any other ACE inhibitor, or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

• Patients who have a history of angioedema.

• During pregnancy

• In breast feeding-women

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 NOVO-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, has been reported. Such possibility should be considered as part of the differential diagnosis of cough (see ADVERSE REACTIONS).

Patient alertness: NOVO-RAMIPRIL 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, 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, or vomiting. 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 - Less Common Cinical Trial Adverse Drug Reactions (<1%), Cardiovascular). Because of the potential fall in blood pressure in these patients, therapy with NOVO-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 NOVO-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. 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 NOVO-RAMIPRIL and/or reduced concomitant diuretic therapy should be considered.

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. 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).

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 NOVO-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 NOVO-RAMIPRIL should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. NOVO- 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. 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, NOVO-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 NOVO-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 (bees, wasps) venom. 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, NOVO- 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. Use of NOVO-RAMIPRIL should include appropriate assessment of renal function. NOVO-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, NOVO-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 NOVO-RAMIPRIL is contraindicated during breast-feeding.

Pediatrics:

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

Geriatrics (> x 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 erythermatosus or scleroderma) or those treated with other drugs that can cause changes in the blood picture.

Renal function monitoring

Use of NOVO-RAMIPRIL should include appropriate assessment of renal function. Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency.

Information for the Patient

Cardiovascular

Hypotension

Patients should be cautioned to report lightheadedness, especially during the first few days of NOVO-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 NOVO-RAMIPRIL and consult with their physician.

Special Populations

Pregnancy

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

DRUG INTERACTIONS

Drug-Drug Interactions

Concomitant Diuretic Therapy

: 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 NOVO-RAMIPRIL can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with NOVO-RAMIPRIL. If it is not possible to discontinue the diuretic, the starting dose of NOVO-RAMIPRIL should be reduced and the patient should be closely observed for several hours following the initial dose and until blood pressure has stabilized (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Agents Increasing Serum Potassium:

Since ramipril decreases 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 Non-steroidal anti-inflammatory agents)

Agents Causing Renin Release:

The antihypertensive effect of ramipril 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 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 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.

Nonsteroidal anti-inflammatory agents

: The antihypertensive effects of ACE inhibitors may be reduced with concomitant administration of nonsteroidal 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 Agents Increasing Serum Potassium)

Antidiabetic agents (e.g. insulin and sulfonylurea derivatives)

: 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.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Essential Hypertension

Dosage of NOVO-RAMIPRIL (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 NOVO- RAMIPRIL may need to be adjusted.

Monotherapy: The recommended initial dosage of NOVO-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 NOVO-RAMIPRIL alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of NOVO-RAMIPRIL.

Concomitant Diuretic Therapy: Symptomatic hypotension occasionally may occur following the initial dose of NOVO- 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 NOVO-RAMIPRIL to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If the diuretic cannot be discontinued, an initial dose of 1.25 mg NOVO- RAMIPRIL should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of NOVO-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 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 10mL/min/1.73m2) the maximum total daily dose of 2.5 mg NOVO-RAMIPRIL should not be exceeded.

OVERDOSAGE

Limited data are available regarding overdosage of ramipril 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. It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

NOVO-RAMIPRIL (ramipril) is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of essential hypertension. Following oral administration, NOVO-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 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 5-20mg of ramipril 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 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 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 and thiazide diuretics used concurrently is greater than that seen with either agent used alone. Abrupt withdrawal of ramipril has not resulted in rapid increase in blood pressure.

Pharmacokinetics

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, 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, 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).

Gender:

Differences in pharmacokinetics based on gender have not been established.

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/1.73m2, 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

Store bottles between 15E- 30EC. Store blister packs between 15E- 25EC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NOVO-RAMIPRIL (ramipril) is available in size no.4 hard gelatin capsules in the following potencies: 1.25 mg: Opaque yellow cap and opaque white body, hard gelatin capsules, printed in black ink N and 1.25 on opposing cap and body portions of the capsules. 2.5 mg: Opaque orange cap and opaque white body, hard gelatin capsules, printed in black ink N and 2.5 on opposing cap and body portions of the capsules. 5 mg: Opaque red cap and opaque white body, hard gelatin capsules, printed in black ink N and 5 on opposing cap and body portions of the capsules. 10 mg: Opaque blue cap and opaque white body, hard gelatin capsules, printed in black ink N and 10 on opposing cap and body portions of the capsules.

COMPOSITION

NOVO-RAMIPRIL (ramipril) capsule composition: 1.25 mg: Each capsule contains medicinal ingredient 1.25 mg ramipril and non-medicinal ingredients: calcium phosphate (dibasic), colloidal silicon dioxide, magnesium hydroxide, magnesium stearate, pregelatinized starch, talc and empty gelatin capsules containing: D & C Yellow No.10, FD & C Yellow No.6, gelatin & titanium dioxide. 2.5 mg: Each capsule contains medicinal ingredient 2.5 mg ramipril and non-medicinal ingredients: calcium phosphate (dibasic), colloidal silicon dioxide, magnesium hydroxide, magnesium stearate, pregelatinized starch, talc and empty gelatin capsules containing: D & C Yellow No.10, FD & C Red No.40, gelatin & titanium dioxide. 5.0 mg: Each capsule contains medicinal ingredient 5.0 mg ramipril and non-medicinal ingredients: calcium phosphate (dibasic), colloidal silicon dioxide, magnesium hydroxide, magnesium stearate, pregelatinized starch, talc and empty gelatin capsules containing: D & C Red No. 33, FD & C Blue No. 1, FD & C Red No. 40, gelatin & titanium dioxide. 10.0 mg Each capsule contains medicinal ingredient 10.0 mg ramipril and non-medicinal ingredients: calcium phosphate (dibasic), colloidal silicon dioxide, magnesium hydroxide, magnesium stearate, pregelatinized starch, talc and empty gelatin capsules containing: D&C Red No. 28, FD & C Blue No. 1, FDA/E172 Black Iron Oxide, gelatin & titanium dioxide.

PACKAGING

NOVO-RAMIPRIL capsules 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg are packaged in bottles of 100 and 500 and in unit dose cartons of 30 capsules.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Ramipril Chemical name: [2S,3aS,6aS]-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]- amino]propanoyl]-octahydro-cyclopenta[b]pyrrole-2-carboxylic acid Molecular formula: C23H32N2O5 Molecular mass: 416.5 Structural formula:

CH3

COOH

N H

OH Physicochemical properties: A white or almost white crystalline powder. Slightly soluble in water, and freely soluble in ethanol and methanol. pH value: 4.44 (0.3% solution) pKa value: 5.64

CLINICAL TRIALS

A single-dose, randomized, two-way study was performed on 23 healthy male subjects, 18 to 55 years of age to evaluate the comparative bioavailability of two formulations of ramipril 10 mg capsules under fasting conditions. The pharmacokinetic data calculated for the two ramipril formulations are tabulated below.

Summary Table of the Comparative Bioavailability Data for Single-Dose Studies Ramipril (N=23) (Amount of product administered: NOVO-RAMIPRIL 1x 10 mg capsules and Altace(r) 1 x 10 mg capsules, under fasting conditions.)

Analyte: Ramipril

aTMAX is expressed as median (range).

bT2 is expressed as arithmetic mean (CV%) only.

• Altace7 10 mg capsules (Hoechst Marion Roussel Canada Inc.), purchased in Canada.

Analyte: Ramiprilat

aTMAX is expressed as median (range).

bT2 is expressed as arithmetic mean (CV%) only.

Altace7 10 mg capsules (Hoechst Marion Roussel Canada Inc.), purchased in Canada. A single-dose, randomized, two-way study was performed on 24 healthy male subjects, 18 to 55 years of age to evaluate the comparative bioavailability of two formulations of ramipril 10 mg capsules under fed conditions. The pharmacokinetic data calculated for the two ramipril formulations are tabulated below.

Summary Table of the Comparative Bioavailability Data for Single-Dose Studies Ramipril (N=22) (Amount of product administered: NOVO-RAMIPRIL 1x 10 mg capsules and Altace(r) 1 x 10 mg capsules, under fed conditions.)

Analyte: Ramipril

aTMAX is expressed as median (range).

bT2 is expressed as arithmetic mean (CV%) only.

Altace7 10 mg capsules (Hoechst Marion Roussel Canada Inc.), purchased in Canada.

Analyte: Ramiprilat

aTMAX is expressed as median (range).

bT2 is expressed as arithmetic mean (CV%) only.

Altace7 10 mg capsules (Hoechst Marion Roussel Canada Inc.), purchased in Canada.

DETAILED PHARMACOLOGY

Mechanism of Action

Effects on Blood Pressure

TOXICOLOGY

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

Table 1 - 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 2 - Chronic Toxicity:

Table 2 - Chronic Toxicity:

Table 2 - Chronic Toxicity:

Table 3 - Reproduction and Teratology

Table 3 - Reproduction and Teratology

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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

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

9. 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.

10. 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.

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

12. Schreiner M, Berendes B, Verho M, et al. Antihypertensive Effficacy, 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.

13. 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, ParallelGroup Study and an Open Single-Blind Study. J of Cardiovascular Pharmacology 1991, 18(Suppl 2): S144-S146.

14. 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.

15. A two-way crossover fasting bioavailability study of NOVO-RAMIPRIL capsules in normal, healthy, non-smoking volunteers. Completed August, 2001. Data on file at Novopharm Limited.

16. A two-way crossover fed bioavailability study of NOVO-RAMIPRIL capsules in normal, healthy, non-smoking volunteers. Completed August, 2001. Data on file at Novopharm Limited.

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Pr

NOVO- RAMIPRIL

(ramipril)

This leaflet is part III of a three-part "Product Monograph" published when NOVO-RAMIPRIL was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about NOVO- RAMIPRIL. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

For Patients with High Blood Pressure

Your doctor has prescribed NOVO-RAMIPRIL, a medication that helps to control blood pressure.

Managing your lifestyle

Keeping your blood pressure controlled

But it takes more than just medication to reduce blood pressure. Discuss the risk factors, and how they apply to your lifestyle, with

your doctor. You may have to modify some of your daily habits to keep your blood pressure down.

Exercise regularly. It will help to keep your weight down, make you feel more energetic and is a good way to deal with stress. If you are not exercising regularly, be sure to discuss a fitness plan with your doctor.

Remember, hypertension is a long-term disease without symptoms. Just because you feel fine does not mean you can stop taking your medication. If you stop, serious complications of the disease may occur. Therefore, you should continue to take NOVO-RAMIPRIL regularly, as prescribed by your doctor.

The "lifestyle" part of your treatment is as important as your medication. By working as a team with your doctor, you can help reduce the risk of complications to maintain the style of life you are accustomed to.

Alcohol: Avoid alcoholic beverages until you have discussed their use with your doctor. Alcohol consumption may alter your blood pressure and/or increase the possibility of dizziness or fainting.

Diet: Generally, avoid fatty foods and food that is high in salt or cholesterol.

Smoking: Avoid it completely.

What it does:

NOVO-RAMIPRIL opens blood vessels to reduce blood pressure, just like the way opening a hose reduces water pressure. It is not,

however, a cure.

When it should not be used:

You have had an allergic reaction to ramipril and/or any components of NOVO-RAMIPRIL capsules (see what are the

important non-medicinal ingredients) or to any other medication of the same group of medicines called ACE (angiotensin

converting enzyme) inhibitors. (see Warnings and Precautions).

You have a history of a condition called angioedema (dysfiguring type of temporary swelling which can be hazardous) (see Side Effects).

What the medicinal ingredient is:

Ramipril

What the nonmedicinal ingredients are:

The qualitative formulation for all potencies of NOVO- RAMIPRIL is: ramipril, calcium phosphate (dibasic), colloidal

silicon dioxide, magnesium hydroxide, magnesium stearate, pregelatinized starch, talc and empty gelatin capsules.

Empty gelatin capsules for all potencies of NOVO-RAMIPRIL are composed of gelatin, titanium dioxide and colouring agents specific to each potency (see below).

1.25 mg: Empty gelatin capsules colouring agents: D & C Yellow No.10, FD & C Yellow No.6, gelatin & titanium dioxide.

2.5 mg: Empty gelatin capsules colouring agents: D & C Yellow No.10, FD & C Red No.40, gelatin & titanium dioxide.

5.0 mg: Empty gelatin capsules colouring agents: D & C Red No. 33, FD & C Blue No. 1, FD & C Red No. 40, gelatin & titanium dioxide.

mg: Empty gelatin capsules colouring agents: D&C Red No. 28, FD & C Blue No. 1, FDA/E172 Black Iron Oxide, gelatin & titanium dioxide.

What dosage forms it comes in:

NOVO-RAMIPRIL (ramipril) is available as a 1.25 mg, 2.5 mg, 5

mg and 10 mg capsule.

WARNINGS AND PRECAUTIONS

Serious Warning and Precautions

NOVO-RAMIPRIL should not be used during pregnancy. If you discover that you are pregnant while taking NOVO-

RAMIPRIL, stop the medication and please contact your

physician as soon as possible.

BEFORE you use NOVO-RAMIPRIL talk to your doctor or pharmacist if:

You are currently taking any other medications, whether on prescription or otherwise (see Interactions with this Medication)?

You should not be taking salt substitutes, potassium

IMPORTANT: PLEASE READ

supplements or potassium containing medicine without the advice of your doctor. If you have to undergo any dental or other surgery, inform the dentist or physician in charge that you are taking this medicine.

You suffer from any other condition?

The presence of other medical problems may affect the use of NOVO-RAMIPRIL. If you have developed heart failure after a heart attack, you may have to limit your physical activities: before you begin exercising, be sure to consult with your doctor. Make sure you tell your doctor if you have any other medical problems, especially if you have diabetes, liver disease, kidney disease, heart or blood vessel disease.

You are pregnant, breast-feeding or thinking of becoming pregnant?

Taking NOVO-RAMIPRIL during pregnancy can cause injury and even death to your baby. This medicine should not be used during pregnancy. If you become pregnant while taking NOVO-RAMIPRIL, stop the medication and report promptly to your doctor as soon as possible. It is possible that NOVO-RAMIPRIL passes into breast milk. You should not breast-feed while taking NOVO-RAMIPRIL.

Remember

Use this drug as directed by your doctor. All drugs can have both helpful and harmful effects. Both depend on

the person and his or her condition. This leaflet alerts

you to some of the times you should call your doctor. Other situations which cannot be predicted can arise. Nothing in this leaflet should stop you from calling your doctor or pharmacist with any questions or concerns you have about NOVO-RAMIPRIL.

INTERACTIONS WITH THIS MEDICATION

Some drugs may have negative effect on NOVO-RAMIPRIL or NOVO-RAMIPRIL may have a negative effect on other drugs. If you are currently taking any other medications, whether on prescription or otherwise, inform your doctor or pharmacist. This is especially important if you are taking diuretics (water pills) or any other medication to reduce blood pressure which may add to the blood pressure lowering effect of NOVO-RAMIPRIL.

Drugs that may interact with NOVO-RAMIPRIL include also agents increasing serum potassium: such as potassium supplements, salt substitutes or medicines which contain potassium. These should be used with caution.

by your doctor.

High Blood Pressure: The recommended initial dosage of NOVO-RAMIPRIL is 2.5 mg once daily. Your doctor will determine the appropriate dosage.

For patients taking diuretics or with impaired kidney function: The recommended initial dosage of NOVO-RAMIPRIL is 1.25 mg daily.

Overdose:

If you take too much NOVO-RAMIPRIL, immediately contact your doctor or go to your nearest hospital emergency department.

Missed Dose:

If you forgot to take your NOVO-RAMIPRIL capsule, take it as

soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Along with its intended action, any medication, including NOVO- RAMIPRIL, may cause side effects. After you have started taking NOVO-RAMIPRIL, it is important that you tell your doctor at once about any unexplained symptom you might experience. Examples of this are unexplained fever, rash, itching, any sign of infection, viral-like symptoms, flu-like symptoms, coughing, sore throat, abdominal pain, loss of appetite, sad mood, jaundice, dizziness, fatigue, or nausea. These side effects may disappear once your system becomes used to the medication. If they persist, discuss this with your doctor. Your medication might have to be reduced or changed.

Dizziness or lightheadedness may occur after the first dose of this medicine. Make sure you know how you react to this medicine before you drive, operate machinery, or do anything requiring you to be alert. If fainting occurs after using NOVO-RAMIPRIL, discontinue use and consult your doctor.

If you are suffering from excessive sweating, vomiting or diarrhea, this may cause you to lose too much water and lead to problems with low blood pressure. See your doctor.

PROPER USE OF THIS MEDICATION

Usual dose:

It is important to take it at the same time every day as prescribed

IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

Angioedema is characterized by swollen mouth, lips, tongue, eyes, extremities, throat or difficulty in swallowing or breathing. Intestinal angioedema may also occur and is characterized by abdominal pain (with or without nausea or vomiting). If you notice swelling or feel pain in these areas, inform your doctor immediately. You should also inform your doctor if you have an unexplained fever, rash or itching.

This is not a complete list of side effects. For any unexpected effects while taking NOVO-RAMIPRIL, contact your doctor or pharmacist.

HOW TO STORE IT

Store in original container: bottles between 15oC to 30oC, blister packs between 15oC to 25oC, and not beyond the date indicated on the container. Keep this medication out of the reach of children.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, Novopharm Limited at:

1-800-268-4127 ext. 5005

or druginfo @novopharm.com

This leaflet was prepared by: Novopharm Limited

30 Novopharm Court Toronto, Ontario Canada, M1B 2K9

Last revised: May 02, 2007.