PMSC-Ramipril Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

pmsc-RAMIPRIL (ramipril) is indicated for:

• Treatment of Essential Hypertension. It may be used alone or in association with thiazide diuretics or with the calcium channel blocker felodipine.

  The safety and efficacy of ramipril in renovascular hypertension have not been established and therefore, its use in this condition is not recommended.

  pmsc-RAMIPRIL can also be tried as an initial agent in those patients in whom use of diuretics and/or beta blockers are contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

  The safety and efficacy of concurrent use of ramipril with antihypertensive agents other than thiazide diuretics have not been established.

• Treatment Following Acute Myocardial Infarction in clinically stable patients with signs of left ventricular dysfunction to improve survival and reduce hospitalizations for heart failure.

  Sufficient experience in the treatment of patients with severe (NYHA class IV) heart failure immediately after myocardial infarction is not yet available (see WARNINGS AND PRECAUTIONS-Cardiovascular, Hypotension).

• Management of Patients at Increased Risk of Cardiovascular Events

  pmsc-RAMIPRIL may be used to reduce the risk of myocardial infarction, stroke or cardiovascular death in patients >55 years of age who are at high risk of cardiovascular events because of a history of coronary artery disease, stroke, peripheral artery disease, or diabetes that is accompanied by ≥1 other cardiovascular risk factor:

  • hypertension,
  • elevated total cholesterol levels,
  • low high-density lipoprotein (HDL) levels,
  • cigarette smoking, or
  • documented microalbuminuria.

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, Pharmacokinetics).

Pediatrics (<18 years of age)

The safety and effectiveness of ramipril in children have not been established. Therefore, pmsc-RAMIPRIL is not indicated in this patient population.

CONTRAINDICATIONS

• Patients who are hypersensitive to this drug, any other angiotensin converting enzyme (ACE) inhibitor, to any ingredient in the formulation or component of the container. For a complete listing of ingredients see DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Patients who have a history of hereditary/idiopathic angioedema, or angioedema with or without treatment with an ACE inhibitor.
• Pregnant and nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women and Nursing Women).
• Patients with hemodynamically relevant bilateral renal artery stenosis, or unilateral in the single kidney (see WARNINGS AND PRECAUTIONS, Renal, Renal impairment).
• Patients with hypotensive states or hemodynamically unstable states.
• Concomitant use with sacubitril/valsartan due to an increased risk of angioedema. Do not initiate pmsc-RAMIPRIL until at least 36 hours have elapsed following the last dose of sacubitril/valsartan. In the case of a switch from pmsc-RAMIPRIL to sacubitril/valsartan, do not start sacubitril/valsartan until at least 36 hours have elapsed following the last dose of pmsc-RAMIPRIL.

• Combination with aliskiren-containing drugs in patients with

  • diabetes mellitus (type 1 or type 2)
  • moderate to severe renal impairment (GFR <60 mL/min/1.73m²)
  • hyperkalemia (>5 mMol/L)
  • congestive heart failure who are hypotensive

[see WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and DRUG INTERACTIONS, Dual Blockade of the Renin- Angiotensin System (RAS)].

• Combination with angiotensin II receptor antagonists (ARBs) in patients with:

  • Diabetes with end organ damage
  • moderate to severe renal impairment (GFR <60 mL/min/1.73m²)
  • hyperkalemia (>5 mMol/L)
  • congestive heart failure who are hypotensive

[see WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and DRUG INTERACTIONS, Dual Blockade of the Renin- Angiotensin System (RAS)].

• Combination with extracorporeal treatments leading to contact of blood with negatively charged surfaces since such use may lead to anaphylactoid reactions. Such extracorporeal treatments include dialysis or hemofiltration with certain high-flux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate (see WARNINGS

  AND PRECAUTIONS, Immune).

WARNINGS AND PRECAUTIONS

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).

Driving a vehicle or performing other hazardous tasks

Some adverse effects (e.g. some symptoms of a reduction in blood pressure (BP) such as light-headedness, dizziness, syncope) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

Patient alertness

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

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of ACE inhibitors, such as pmsc-RAMIPRIL, or of ARBs with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR<60 mL/min/1.73m²). Therefore, the use of pmsc-RAMIPRIL in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS). The use of pmsc-RAMIPRIL in combination with an ARB is contraindicated in patients with diabetic nephropathy (see CONTRAINDICATIONS). Further, co-administration of ACE inhibitors, including pmsc-RAMIPRIL, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia (see DRUG INTERACTIONS).

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, vomiting, or in other situations in which a significant activation of the RAS is to be anticipated such as in patients with severe, and particularly malignant, hypertension, in patients with hemodynamically relevant left- ventricular outflow impediment (e.g., stenosis of the aortic valve) or in patients with hemodynamically relevant renal artery stenosis. All patients should be cautioned about this potential excessive fall in BP and advised to consult their physician.

Generally, it is recommended that dehydration, hypovolemia 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 pmsc-RAMIPRIL must only be started or continued if appropriate steps are taken concurrently to prevent an excessive fall in BP and deterioration of renal function.

In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in BP could result in a myocardial infarction or cerebrovascular accident (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions). Because of the potential fall in BP in these patients, therapy with pmsc-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 pmsc-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 BP has increased after volume expansion in hypertensive patients. However, lower doses of pmsc-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 pmsc-RAMIPRIL (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Treatment Following Acute Myocardial Infarction, and DOSAGE & ADMINISTRATION, Recommended Dose and Dosage Adjustment, Treatment Following Acute Myocardial Infarction).

pmsc-RAMIPRIL may lower the state of patient alertness and/or reactivity; particularly at the start of treatment (see ADVERSE REACTIONS). Patients should be cautioned to report light-headedness, especially during the first few days of pmsc-RAMIPRIL therapy. If actual syncope occurs, the patients should be told to discontinue the drug and consult with their physician.

Endocrine and metabolism

Hyperkalemia and Potassium-Sparing Diuretics

Elevated serum potassium (>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).

Hematologic

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).

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, Post-Market Adverse Drug Reactions).

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 pmsc-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 pmsc-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 pmsc-RAMIPRIL may be either increased or reduced. In addition, in patients in whom severe liver cirrhosis with oedema and/or ascites is present, the RAS may be significantly activated. pmsc-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 pmsc-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 or Extremities

Angioedema has been reported in patients with ACE inhibitors including ramipril.

Life threatening angioedema has been reported in patients with ACE inhibitors, including ramipril. The overall incidence is 0.1 - 0.2%. Angioedema involving the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors.

Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, pmsc-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 0.3-0.5 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).

An increased risk of angioedema is possible with concomitant use of other drugs which may cause angioedema.

Concomitant use of mTOR inhibitors, DPP-IV inhibitors and NEP inhibitors

Patients taking a concomitant mTOR inhibitor (e.g. sirolimus, everolimus, temsirolimus), DPP-IV inhibitor (e.g. sitagliptin) or neutral endopeptidase (NEP) inhibitor may be at increased risk for angioedema. Caution should be used when initiating ACE inhibitor therapy in patients already taking a mTOR, DPP-IV or NEP inhibitor or vice versa (see DRUG INTERACTIONS).

Concomitant use of sacubitril/valsartan

A potential increased risk of angioedema has been reported with concomitant use of sacubitril/valsartan and ACE inhibitors. (see CONTRAINDICATIONS)

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 1st dose of pmsc-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. Therefore, the use of pmsc-RAMIPRIL in patients dialyzed with high-flux membranes is contraindicated (see CONTRAINDICATIONS). 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. If such treatment is required, 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. Therefore, the use of pmsc-RAMIPRIL in patients receiving low density lipoprotein apheresis with dextran sulfate is contraindicated (see CONTRAINDICATIONS). If such treatment is required, consideration should be given to using a different type of apheresis or a different class of antihypertensive agents.

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 ≥24 hours, but they have reappeared upon inadvertent rechallenge.

Nitritoid Reactions – Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ramipril (see DRUG INTERACTIONS).

Peri-Operative Considerations

Surgery/anesthesia

In patients undergoing surgery or anesthesia with agents producing hypotension, 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

Renal impairment

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the RAAS, 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.

The use of ACE inhibitors – including ramipril – or ARBs with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus (type 1 or 2), moderate to severe renal impairment (GFR<60 mL/min/1.73m²), hyperkalemia (>5 mMol/L) or congestive heart failurewho are hypotensive (see CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE inhibitors, or aliskiren-containing drugs).

Concomitant use of ACE inhibitors – including ramipril, with ARBs or other ACE inhibitors is contraindicated in patients with diabetes with end organ damage, moderate to severe kidney insufficiency (GFR <60 mL/min/1.73m²), hyperkalemia (>5mMol/L) or congestive heart failure who are hypotensive see CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE inhibitors, or aliskiren-containing drugs).

Use of pmsc-RAMIPRIL should include appropriate assessment of renal function.

pmsc-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, pmsc-RAMIPRIL should be discontinued as soon as possible, and, if appropriate, alternative therapy should be started. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

The use of ACE inhibitors is contraindicated during pregnancy.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have been reported following exposure in the first trimester of pregnancy.

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.

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 BP 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 (2,500 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 (1,250 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 has been reported in human milk. The use of pmsc-RAMIPRIL is contraindicated during breastfeeding (see CONTRAINDICATIONS)

Pediatrics (< 18 years of age)

The safety and effectiveness of ramipril in children have not been established. Therefore, pmsc-RAMIPRIL is not indicated in this patient population.

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. Evaluation of renal function at the beginning of treatment is recommended (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, Corticosteroids, Procainamide, Cytostatics and other substances that may change the blood picture).

Renal function monitoring

Use of pmsc-RAMIPRIL should include appropriate assessment of renal function, particularly in the initial weeks of treatment. 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 (atherosclerotic renal artery stenosis (AS-RAS) and fibromuscular dysplasia (FMD)). In patients with hemodynamically relevant unilateral renal
• artery stenosis, even a small increase in serum creatinine may be indicative of unilateral loss of renal function
• impairment of renal function
• kidney transplant
• elderly patients

Electrolyte monitoring

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

ADVERSE REACTIONS

Adverse Drug Reaction Overview

As ramipril is an antihypertensive, the most common adverse reactions are effects secondary to its blood-pressure-lowering action.

In long-term safety studies in patients with hypertension the most commonly reported serious adverse reactions were myocardial infarction (0.3%); edema (0.2%); hypotension (0.1%); cerebrovascular accident (0.1%); and syncope (0.1%). Angioedema occurred in 0.1% patients treated with ramipril and a diuretic.

The most frequent adverse events (AEs) occurring in these trials were: headache (15.1%); dizziness (3.7%); asthenia (3.7%); chest pain (2.0%); nausea (1.8%); peripheral edema (1.8%);

somnolence (1.7%); impotence (1.5%); rash (1.4%); arthritis (1.1%); and dyspnea (1.1%). Discontinuation of therapy due to clinical AEs was required in 0.8% of patients treated with ramipril. Cough caused discontinuation of therapy in approximately 1% of patients in North American controlled clinical trials.

Post-Acute Myocardial Infarction Adverse reactions (AIRE Study) considered possibly/probably related to study drug that occurred in >1% of patients and more frequently on ramipril were: Hypotension, Cough increased, Dizziness/Vertigo, Nausea/Vomiting, Angina pectoris, Postural hypotension, Syncope, Heart failure, Severe/resistant heart failure, Myocardial infarct, Vomiting, Headache, Abnormal kidney function, Abnormal chest pain and Diarrhea. Discontinuation of therapy due to adverse reactions was required in 36.7% of post-AMI patients taking ramipril compared to 40.8% of patients receiving placebo.

The safety profile of ramipril in patients at Increased Risk of Cardiovascular Events (HOPE Study) was consistent with the post-marketing surveillance experience. Reasons for discontinuation of therapy were cough (ramipril 7.3%, placebo 1.8%), hypotension/dizziness (ramipril 1.9%, placebo 1.5%) and edema (ramipril 0.4%, placebo 0.2%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Essential Hypertension

Ramipril was evaluated for safety in > 4000 hypertensive patients. Almost 500 elderly patients participated in controlled trials. Long-term safety was assessed in almost 700 patients treated for

≥1 year. There was no increase in the incidence of AEs in elderly patients given the same daily dose. The overall frequency of AEs was not related to duration of therapy or total daily dose.

Serious AEs occurring in North American placebo-controlled clinical trials with ramipril monotherapy in hypertension (n=972) were: myocardial infarction (0.3%); edema (0.2%); hypotension (0.1%); cerebrovascular accident (0.1%); syncope (0.1%). Among all North American ramipril patients (n=1,244), angioedema occurred in 0.1% patients treated with ramipril and a diuretic.

The most frequent AEs occurring in these trials with ramipril monotherapy in hypertensive patients that were treated for ≥1 year (n=651) were: headache (15.1%); dizziness (3.7%);

asthenia (3.7%); chest pain (2.0%); nausea (1.8%); peripheral edema (1.8%); somnolence (1.7%); impotence (1.5%); rash (1.4%); arthritis (1.1%); dyspnea (1.1%). Discontinuation of therapy due to clinical AEs was required in 5 patients (0.8%).

In placebo-controlled trials, an excess of upper respiratory infection and flu syndrome was seen in the ramipril group. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of these patients requiring discontinuation of treatment. Approximately 1% of patients treated with ramipril monotherapy in North American controlled clinical trials (n=972) have required discontinuation because of cough.

Treatment Following Acute Myocardial Infarction

In a controlled clinical trial, 1,004 post-AMI patients received ramipril. In both the ramipril and placebo groups, myocardial infarction, heart failure, atrial fibrillation, peripheral vascular disease and urinary tract infection were more common in elderly than in younger patients. Gastrointestinal disturbances were more frequent in elderly patients on ramipril. Cough and hypotension were more frequent in women receiving ramipril.

Adverse events (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in >1% of stabilized patients with clinical signs of heart failure treated with ramipril following an acute myocardial infarction are shown below. The incidences represent the experiences from the AIRE (Acute Infarction Ramipril Efficacy) study; the follow-up time was 6 to 48 months (mean follow up = 15 months).

Table 1: Percentage of Patients with Adverse Events Possibly/Probably Related to Study Drug in the Placebo-Controlled (AIRE) Mortality Study

Table 2: Percentage of Patients with Serious Adverse Events Possibly related to Study Drug in the Placebo-Controlled (AIRE) Mortality Study

Isolated cases of death were reported with the use of ramipril that appeared to be related to hypotension (including first dose effects), but many of these were difficult to differentiate from progression of underlying disease (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).

Discontinuation of therapy due to adverse reactions was required in 36.7% (368/1,004) post-AMI patients taking ramipril, compared to 40.8% (401/982) patients receiving placebo.

Management of Patients at Increased Risk of Cardiovascular Events

The safety profile of ramipril in the Heart Outcome Prevention Evaluation (HOPE) study, based on 4645 patients treated with ramipril, was consistent with the post-marketing surveillance experience. Reasons for stopping treatment, where the incidence was greater in the ramipril than in the placebo group, were cough (ramipril 7.3%, placebo 1.8%), hypotension/dizziness (ramipril 1.9%, placebo 1.5%) and edema (ramipril 0.4%, placebo 0.2%).

Less Common Adverse Drug Reactions (<1%)

Clinical adverse events occurring in <1% of patients treated with ramipril in controlled clinical trials are listed below by body system:

Body as a whole: angioedema.

Cardiovascular: angina pectoris, arrhythmia, chest pain, disturbed orthostatic regulation, exacerbation of perfusion disturbances due to vascular stenosis, flushing, myocardial infarction, palpitations, symptomatic hypotension, syncope, tachycardia, vascular stenosis.

CNS: anxiety, amnesia, confusion, convulsions, depression, disorders of balance, hearing loss, impaired hearing, insomnia, light-headedness, nervousness, neuralgia, neuropathy, paresthesia, polyneuritis, restlessness, sleep disturbances, somnolence, tinnitus, tremor, vertigo, vision disturbances (including blurred vision).

Dermatologic: apparent hypersensitivity reactions (with manifestations of urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura.

In addition, the following cutaneous or mucosal reactions may occur: erythroderma/exfoliative dermatitis, exacerbation of psoriasis, lichenoid exanthema, pemphigoid exanthema and enanthema, maculopapular rash, maculo-papular exanthema, onycholysis, psoriasiform exanthema, reversible alopecia, and toxic epidermal necrolysis or nycholysis.

Gastrointestinal: abdominal discomfort, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, digestive disturbances, decreased appetite, dry mouth, dyspepsia, dysphagia, gastritis, gastroenteritis, glossitis, increased levels of pancreatic enzymes, increased salivation, intestinal angioedema, nausea, pancreatitis (cases of fatal outcome have been very exceptionally reported), smell and taste disturbance, upper abdominal pain, vomiting.

Hematologic: agranulocytosis, eosinophilia, leukopenia, thrombocytopenia (see WARNINGS AND PRECAUTIONS, Hematologic, Neutropenia/agranulocytosis section).

Hepatobiliary: hepatic failure, increased hepatic enzymes and/or conjugated bilirubin in isolated cases liver damage (including acute liver failure) may occur. 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.

Renal: impaired renal function, oliguria and acute renal failure. Increases in blood urea nitrogen (BUN) and serum creatinine. Rarely, a deterioration of pre-existing proteinuria may develop (though ACE inhibitors usually reduce proteinuria) or an increase in urinary output (in connection with an improvement in cardiac performance).

Respiratory: bronchitis, bronchospasm (including aggravated asthma), increased cough, nasal congestion, sinusitis.

Other: arthralgia, arthritis, conjunctivitis, depressed mood, dyspnea, edema, epistaxis, impotence, increased sweating, loss of taste, malaise, muscle cramps, myalgia, reduced libido, transient erectile impotence, weight gain.

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur.

Abnormal Hematologic and Clinical Chemistry Findings

The following abnormal hematologic and clinical chemistry findings have been reported: decreases in red blood cell count, hemoglobin or hematocrit; elevations of liver enzymes, serum bilirubin, uric acid, blood glucose; hyponatremia; increased creatinine; increases in BUN; proteinuria and significant increases in serum potassium.

Post-Market Adverse Drug Reaction

Body as a whole: anaphylactoid reactions, angioedema (cases of fatal outcome have been reported), fatigue.

Cardiovascular: cerebrovascular disorders (including ischaemic stroke and transient ischaemic attack).

CNS: attention disturbances, burning sensation (mainly to skin of face or extremities), impaired psychomotor skills (impaired reactions), precipitation or intensification of Raynaud’s phenomenon, smell disturbances.

Dermatologic: erythema multiforms, exacerbation of psoriasis, lichenoid exanthema, pemphigoid exanthema and enanthema, pemphigus, reversible alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Endocrine: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Gastrointestinal: aphthous stomatitis

Hematologic: bone marrow depression and hemolytic anemia (see WARNINGS AND PRECAUTIONS, Hematologic, Neutropenia/agranulocytosis section), pancytopenia.

Hepatobiliary: acute hepatic failure, cholestatic or cytolytic jaundice, hepatitis (cases of fatal outcome have been very exceptional), in isolated cases liver damage (including acute liver failure) may occur.

Laboratory test findings: decrease in blood sodium.

Other: gynaecomastia, positive antinuclear antibodies (ANA).

DRUG INTERACTIONS

Drug-Drug Interactions

Table 3: Established or potential drug-drug interactions

C = Case Study; CT = Clinical Trial; T = Theoretical

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Essential Hypertension

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

Monotherapy

The recommended initial dosage of pmsc-RAMIPRIL in patients not on diuretics is 2.5 mg once daily. Dosage should be adjusted according to BP response, generally, at intervals of ≥2 weeks. The usual dose range is 2.5 to 10 mg once daily. The maximum daily dose is 20 mg.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring BP 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 BP is not controlled with pmsc-RAMIPRIL alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of pmsc-RAMIPRIL.

Concomitant Diuretic Therapy

Symptomatic hypotension occasionally may occur following the initial dose of pmsc-RAMIPRIL and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for 2 to 3 days before beginning therapy with pmsc-RAMIPRIL to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If the diuretic cannot be discontinued, an initial dose of 1.25 mg pmsc-RAMIPRIL should be used with careful medical supervision for several hours and until BP has stabilized. The dosage of pmsc-RAMIPRIL should subsequently be titrated (as described above) to the optimal response.

Use in renal impairment

For patients with a creatinine clearance <40mL/min/1.73m² (serum creatinine >2.5 mg/dL), the recommended initial dose is 1.25 mg pmsc-RAMIPRIL once daily. Dosage may be titrated upward until BP is controlled or to a maximum total daily dose of 5 mg. In patients with severe renal impairment (creatinine clearance <10 mL/min/1.73m²), the maximum total daily dose is 2.5 mg pmsc-RAMIPRIL.

Use in hepatic impairment

The response to the treatment with pmsc-RAMIPRIL may be either increased or reduced. Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg.

Treatment Following Acute Myocardial Infarction

Dosage of pmsc-RAMIPRIL must be individualized. Initiation of therapy requires consideration of concomitant medication and baseline BP and should be instituted under close medical supervision, usually in a hospital, 3 to 10 days following an acute myocardial infarction (AMI) in hemodynamically stable patients with clinical signs of heart failure.

The recommended initial dosage of pmsc-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 1 to 3 days. The maximum daily dose of pmsc-RAMIPRIL is 5 mg twice daily (b.i.d.).

Due to the risk of angioedema when used concomitantly with sacubitril/valsartan, pmsc-RAMIPRIL must not be started until 36 hours has passed following the last dose of sacubitril/valsartan (see CONTRAINDICATIONS).

After the initial dose of pmsc-RAMIPRIL, the patient should be observed under medical supervision for ≥ 2 hours and until BP 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 BP may occur particularly in the following:

• after the initial dose of pmsc-RAMIPRIL,
• after every first increase of dose of pmsc-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 pmsc-RAMIPRIL in these patients.

Use in renal impairment

In patients with impaired renal function (creatinine clearance of 20 to 50 mL/min/1.73 m² body surface area), the initial recommended dosage is generally 1.25 mg pmsc-RAMIPRIL once daily. This dosage may be increased with caution up to 2.5 mg pmsc-RAMIPRIL given as 1.25 mg pmsc-RAMIPRIL twice daily, depending upon clinical response and tolerability.

Insufficient data is available concerning the use of pmsc-RAMIPRIL following AMI 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 pmsc-RAMIPRIL following AMI in patients with heart failure and hepatic dysfunction. Dose reduction and careful monitoring of these patients is required (see ACTIONS & CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic). The response to the treatment with pmsc-RAMIPRIL may be either increased or reduced. Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg.

Management of Patients at Increased Risk of Cardiovascular Events

The recommended initial dose is 2.5 mg pmsc-RAMIPRIL once daily. Depending on the tolerability, the dose can be gradually increased. It is recommended to double the dose after 1 week of treatment and - after another 3 weeks - to increase it to 10 mg. The usual maintenance dose is 10 mg pmsc-RAMIPRIL daily (see ACTION AND CLINICAL PHARMACOLOGY and WARNINGS AND PRECAUTIONS).

Use in renal and hepatic impairment

Dosage recommendations for special risk groups such as patients with renal 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).

In hepatic impairment, the response to the treatment with pmsc-RAMIPRIL may be either increased or reduced. Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg.

OVERDOSAGE

Limited data are available regarding overdosage with ramipril in humans; only 2 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 vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management

Primary detoxification by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the first 30 minutes). In the event of hypotension administration of α1- 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, hemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or hemofiltration 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, and for the management of patients at increased risk of cardiovascular events.

Following oral administration, ramipril is rapidly hydrolyzed to ramiprilat, its principal active metabolite.

ACE 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, Endocrine and Metabolism, 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 BP 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 to 20 mg ramipril lowered BP within 1 to 2 hours, with peak reductions achieved 3 to 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 (>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, BP reductions at the time of morning trough blood levels were greater with the divided regimen.

While the mechanism through which ramipril lowers BP appears to result primarily from suppression of the renin-angiotensin-aldosterone system (RAAS), 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 BP.

Pharmacokinetics

Table 4: 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 ≤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 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 to 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 to 18 hours, and the terminal elimination phase has a prolonged half-life of >50 hours. After multiple daily doses of ramipril 5 to 10 mg, the half-life of ramiprilat concentrations was 13 to 17 hours, but was considerably prolonged at 2.5 mg (27 to 36 hours).

After once daily dosing, steady state plasma concentrations of ramiprilat are reached by the 4th dose. Steady-state concentrations of ramiprilat are higher than those seen after the 1st 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 to 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 ACE 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 C_max 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 between 15°C and 30°C. Protect from moisture. Keep out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Capsules

Composition

pmsc-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 pmsc-RAMIPRIL capsules are: Gelatin, hydrophobic colloidal anhydrous, iron oxide yellow, ponceau, pregelatinized Starch, patent blue V, silica, sodium lauryl sulfate and titanium dioxide.

Hard Gelatin Capsules for all potencies of pmsc-RAMIPRIL are composed of Gelatin and coloring agents specific to each potency (see below).

Composition of pmsc-RAMIPRIL capsules

• pmsc-RAMIPRIL (ramipril) 1.25 mg: Yellow / white size ‘4’ hard gelatin capsules imprinted with ‘RP’ on yellow cap and ‘1.25’ on white body with black edible ink filled with white to almost white powder.
• pmsc-RAMIPRIL (ramipril) 2.5 mg: Orange / white size ‘4’ hard gelatin capsules imprinted with ‘RP’ on orange cap and ‘2.5’ on white body with black edible ink filled with white to almost white powder.
• pmsc-RAMIPRIL (ramipril) 5 mg: Red / white size ‘4’ hard gelatin capsules imprinted with ‘RP’ on red cap and ‘5’ on white body with black edible ink filled with white to almost white powder.
• pmsc-RAMIPRIL (ramipril) 10 mg: Blue / white size ‘4’ hard gelatin capsules imprinted with ‘RP’ on blue cap and ‘10’ on white body with black edible ink filled with white to almost white powder.

Packaging

pmsc-RAMIPRIL capsules 1.25 mg, 2.5 mg, 5 mg, 10 mg are packaged in Blister Pack of

3 x 10 and HDPE bottle of 30, 100, 500 and 1000.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ramipril

Chemical name: (2S, 3aS, 6aS)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl] amino] propanoyl] octahydrocyclopenta [b] pyrrole-2-carboxylic acid

Molecular formula: C23H32N2O5

Molecular mass: 416.5 g/mol

Structural formula:

Physicochemical properties

Description: White or almost white, crystalline powder.

Solubility: Sparingly soluble in water, freely soluble in methanol.

CLINICAL TRIALS

Comparative Bioavailability Data

A double blind, randomized, two-treatment, two-sequence, two-period, crossover, single-dose comparative oral bioavailability study of Ramipril capsules BP 5 mg (Test) of Pharmascience Inc. and Altace (Ramipril capsules) 5 mg (Reference) of Sanofi – aventis Canada Inc., Canada in 46 healthy, adult male human subjects under fasting conditions.

Summary Table of the Comparative Bio-availability Data

*pmsc-RAMIPRIL capsules 5 mg, manufactured by Pharmascience Inc.

^† ALTACE^® capsules 5 mg (Reference) manufactured by Sanofi – aventis Canada Inc., Canada were purchased in Canada

^§ Expressed as the Median (Range) instead of Arithmetic Mean (%CV)

^$ Expressed as arithmetic mean (%CV) only.

Comparative Bioavailability Data

A double blind, randomized, two treatment, two sequence, two period, cross-over, single-dose comparative oral bioavailability study of Ramipril capsules BP 10 mg (Test) of Pharmascience Inc. and Altace Capsules 10 mg (Reference) of Aventis Pharma Inc., Canada in 42 healthy, adult male human subjects under fasting conditions.

Summary Table of the Comparative Bio-availability Data

*pmsc-RAMIPRIL capsules 10 mg, manufactured by Pharmascience Inc.

^† ALTACE^® capsules 10 mg (Reference) manufactured by Sanofi – aventis Canada Inc., Canada were purchased in Canada

^§ Expressed as the Median (Range) instead of Arithmetic Mean (%CV)

^$ Expressed as arithmetic mean (%CV) only.

Patients at increased risk of cardiovascular events:

The effects of ramipril were assessed in patients who were at high risk for cardiovascular (CV) events but did not have left ventricular dysfunction or heart failure. The Heart Outcome Prevention Evaluation (HOPE) study included 9,297 patients >55 years of age with a history of coronary artery disease, stroke, peripheral vascular disease or diabetes mellitus plus ≥1 additional cardiovascular risk factor:

• hypertension,
• elevated total cholesterol levels,
• low high-density lipoprotein (HDL) cholesterol levels,
• cigarette smoking, or
• documented microalbuminuria.

Patients were excluded if they:

• had heart failure,
• had low ejection fraction (<0.40),
• were taking an angiotensin converting enzyme (ACE) inhibitor or vitamin E,
• had uncontrolled hypertension or overt nephropathy, or
• had had a myocardial infarction (MI) or stroke within 4 weeks before the study began.

The patients were randomly assigned to receive ramipril 10 mg once daily or matching placebo for a mean of 5 years.

Due to the positive outcome, the study was terminated prematurely by an independent monitoring board. The primary end point, the composite of death from CV causes, MI and stroke was reached by a total of 651 ramipril-treated patients (14%), as compared to 826 placebo-treated patients (17.8%) (relative risk (RR) 0.78, P<0.001). When analysed separately, the rates of individual component of the composite primary outcome in patients treated with ramipril and placebo were as follows: death from CV causes 6.1% vs. 8.1% (RR 0.74, p<0.001), MI 9.9% vs. 12.3% (RR 0.80, p<0.001) and stroke 3.4% vs. 4.9% of patients (RR 0.68, p<0.001), respectively.

Permanent discontinuation of treatment occurred in 28.9% of the ramipril-treated patients vs. 27.3% of placebo-treated patients. The reasons for stopping the treatment, where the incidence was greater in the ramipril than in the placebo group, were cough (ramipril 7.3%, placebo 1.8%), hypotension/dizziness (ramipril 1.9%, placebo 1.5%) and edema (ramipril 0.4%, placebo 0.2%).

DETAILED PHARMACOLOGY

Table 5: Mechanism of Action

Table 7: Pharmacokinetics and Bioavailability

TOXICOLOGY

Acute Toxicity

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

The symptoms observed in mice were decreased spontaneous activity, crouching, hypothermia, dyspnea, and clonic convulsions; deaths occurred within 30 minutes after i.v. 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 i.v. administration similar signs occurred as in mice; the sign of lethal toxicity was clonic convulsions (i.v. administration).

Table 9 - Chronic Toxicity

Table 10- 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 ≤1000 mg/kg/day and to Wistar rats at doses ≤500 mg/kg/day.

REFERENCES

^PrALTACE^® (Capsules, 1.25 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg), Submission Control Number: 239641, Product Monograph, Bausch Health, Canada Inc. January 8, 2021