Ramipril Capsules

mg, 2.5 mg, 5.0 mg and 10.0 mg

ANGIOTENSIN CONVERTING ENZYME INHIBITOR

APOTEX INC. DATE OF PREPARATION:

Signet Drive December 12, 2006

Weston, Ontario M9L 1T9

Control Numbers 085886 & 091920

Table of Contents

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 15 ACTION AND CLINICAL PHARMACOLOGY 15 STORAGE AND STABILITY 18 DOSAGE FORMS, COMPOSITION AND PACKAGING 18

PART II: SCIENTIFIC INFORMATION 20

PHARMACEUTICAL INFORMATION 20 CLINICAL TRIALS. 21 DETAILED PHARMACOLOGY 25 TOXICOLOGY. 27 REFERENCES 32

PART III: CONSUMER INFORMATION 34

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APO-RAMIPRIL

Ramipril Capsules

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

APO-RAMIPRIL (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

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 APO-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

APO-RAMIPRIL (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. Because of the potential fall in blood pressure in these patients, therapy with APO-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 APO-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 APO-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 APO-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 APO-RAMIPRIL should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. APO- 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, APO-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 APO-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, APO- 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 APO-RAMIPRIL should include appropriate assessment of renal function. APO-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, APO-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 APO-RAMIPRIL is contraindicated during breast-feeding.

Pediatrics

The safety and effectiveness of ramipril 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.

Renal function monitoring

Use of APO-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 APO-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 APO-RAMIPRIL and consult with their physician.

Special Populations

Pregnancy: Since the use of APO-RAMIPRIL during pregnancy can cause injury and even death of the developing foetus, patients should be advised report promptly to their physician if they become pregnant and the use of APO-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 APO-RAMIPRIL (ramipril) can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with APO- RAMIPRIL. If it is not possible to discontinue the diuretic, the starting dose of APO-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 APO-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 APO-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.

Non-steroidal anti-inflammatory agents:

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 Agents Increasing Serum Potassium)

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.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Essential Hypertension

Dosage of APO-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 APO-RAMIPRIL may need to be adjusted.

Monotherapy

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

Concomitant Diuretic Therapy

Symptomatic hypotension occasionally may occur following the initial dose of APO-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 APO-RAMIPRIL to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If the diuretic cannot be discontinued, an initial dose of 1.25 mg APO-RAMIPRIL should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of APO-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 APO-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 APO-RAMIPRIL should not be exceeded.

Management of Patients at Increased Risk of Cardiovascular Events

Recommended initial dose: 2.5 mg of APO-RAMIPRIL once daily. Depending on the tolerability, the dose is gradually increased. It is recommended to double the dose after one week of treatment and - after another three weeks - to increase it to 10 mg. Usual maintenance dose: 10 mg of APO-RAMIPRIL daily (see ACTION AND CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS). Dosage recommendations for special risk groups such as patients with renal or hepatic impairment, or at an increased risk of hypotension (fluid or salt depletion, treated with diuretics) are to be followed as previously described (see WARNINGS AND PRECAUTIONS).

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

APO-RAMIPRIL (ramipril) is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of essential hypertension and for the management of patients at increased risk of cardiovascular events. Following oral administration, APO-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 APO-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 5-20 mg 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 APO-RAMIPRIL lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system, APO-RAMIPRIL has an antihypertensive effect even in patients with low-renin hypertension. The antihypertensive effect of APO-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

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 it's 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).

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

Store at room temperature, 15-30degC (59-86degF) in a well-closed container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

APO-RAMIPRIL (ramipril) 1.25 mg is available as white/yellow size #4 capsules, imprinted with "APO 1.25" in black edible ink and containing 1.25 mg ramipril. Available in bottles of 100's. APO-RAMIPRIL (ramipril) 2.5 mg is available as white/orange size #4 capsules, imprinted with "APO 2.5" in black edible ink and containing 2.5 mg ramipril. Available in bottles of 100's. APO-RAMIPRIL (ramipril) 5 mg is available as white/red size #4 capsules, imprinted with "APO 5" in black edible ink and containing 5 mg ramipril. Available in bottles of 100's. APO-RAMIPRIL (ramipril) 10 mg is available as white/blue size #4 capsules, imprinted with "APO 10" in black edible ink and containing 10 mg ramipril. Available in bottles of 100's.

Composition

APO-RAMIPRIL capsules 1.25 mg, 2.5 mg, 5.0 mg, and 10.0 mg contain the medicinal ingredient ramipril in quantities of 1.25 mg, 2.5 mg, 5.0 mg, and 10.0 mg respectively. The qualitative formulation for all potencies of APO-RAMIPRIL is: ramipril, lactose monohydrate (spray-dried), magnesium stearate, talc and empty gelatin capsules. Empty gelatin capsules for all potencies of APO-RAMIPRIL are composed of gelatin and coloring agents specific to each potency (see below).