1 INDICATIONS AND USAGE Ramipril Capsules are an angiotensin converting enzyme (ACE) inhibitor indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

It may be used alone or in combination with thiazide diuretics.

( 1.1 ).

In patients 55 years or older at high risk of developing a major cardiovascular event, Ramipril Capsules are indicated to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes (1.2).

Ramipril Capsules indicated in stable patients who have demonstrated clinical signs of congestive heart failure post-myocardial infarction (1.3).

1.1 Hypertension Ramipril capsules are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Ramipril capsules may be used alone or in combination with thiazide diuretics.

1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes Ramipril capsules are indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes.

Ramipril capsules can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, or lipid-lowering therapy) [see Clinical Studies (14.2) ].

1.3 Heart Failure Post-Myocardial Infarction Ramipril capsules are indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction.

Administration of ramipril capsules to such patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure [see Clinical Studies ( 14.3 )].

1.1 Hypertension Ramipril capsules are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Ramipril capsules may be used alone or in combination with thiazide diuretics.

1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes Ramipril capsules are indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes.

Ramipril capsules can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, or lipid-lowering therapy) [see Clinical Studies (14.2) ].

1.3 Heart Failure Post-Myocardial Infarction Ramipril capsules are indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction.

Administration of ramipril capsules to such patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure [see Clinical Studies ( 14.3 )].

6 ADVERSE REACTIONS The most common adverse reactions in patients with hypertension included headache, dizziness, fatigue, and cough ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact CorePharma LLC.

at 732-419-8800 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypertension Ramipril has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S.

controlled trials, and 1107 were studied in foreign controlled trials.

Almost 700 of these patients were treated for at least one year.

The overall incidence of reported adverse events was similar in ramipril and placebo patients.

The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in ramipril patients than in patients given placebo.

Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg - 20 mg.

Discontinuation of therapy because of a side effect was required in approximately 3% of U.S.

patients treated with ramipril.

The most common reasons for discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%).

Of observed side effects considered possibly or probably related to study drug that occurred in U.S.

placebo-controlled trials in more than 1% of patients treated with ramipril, only asthenia (fatigue) was more common on ramipril than placebo (2% [n=13/651] vs.

1% [n=2/286], respectively).

In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the ramipril group, not attributed at that time to ramipril.

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 patients requiring discontinuation of treatment.

Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes HOPE Study Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment.

The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial.

The rate of angioedema was the same as in previous clinical trials [see Warnings and Precautions (5.1) ].

Table 1.

Reasons for Discontinuation or Temporary Interruption of Treatment—HOPE Study Placebo (N=4652) Ramipril (N=4645) Discontinuation at any time 32% 34% Permanent discontinuation 28% 29% Reasons for stopping Cough 2% 7% Hypotension or dizziness 1.5% 1.9% Angioedema 0.1% 0.3% Heart Failure Post-Myocardial Infarction AIRE Study Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on Ramipril capsules are shown below.

The incidences are from the AIRE study.

The follow-up time was between 6 and 46 months for this study.

Table 2.

Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-Controlled (AIRE) Mortality Study Adverse Event Placebo (N=982) Ramipril Capsules (N=1004) Hypotension 5% 11% Cough increased 4% 8% Dizziness 3% 4% Angina pectoris 2% 3% Nausea 1% 2% Postural hypotension 1% 2% Syncope 1% 2% Vomiting 0.5% 2% Vertigo 0.7% 2% Abnormal kidney function 0.5% 1% Diarrhea 0.4% 1% Other Adverse Reactions Other adverse reactions reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in post-marketing experience, include thefollowing (in some, a causal relationship to drug is uncertain): Body as a whole: Anaphylactoid reactions [ see Warnings and Precautions ( 5.1 ) ].

Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S.

trials) [ see Warnings and Precautions ( 5.5 ) ], syncope, and palpitations.

Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia.

Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic.

Renal: Acute renal failure.

Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking ramipril, particularly when ramipril was given concomitantly with a diuretic [ see Warnings and Precautions ( 5.3 ) ].

Angioneurotic edema: Angioneurotic edema has been reported in 0.3% of patients in U.S.

clinical trials of ramipril [ see Warnings and Precautions ( 5.1 ) ].

Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation, and taste disturbance.

Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome.

Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.

Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.

Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.

Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.

6.2 Post-Marketing Experience In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during ramipril therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin.

The causal relationship is unknown.

6.3 Clinical Laboratory Test Findings Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and a diuretic.

Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with a diuretic.

None of these increases required discontinuation of treatment.

Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis [ see Warnings and Precautions ( 5.3 ) ].

As ramipril decreases aldosterone secretion, elevation of serum potassium can occur.

Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient’s serum potassium frequently [ see Warnings and Precautions ( 5.8 ) ].

Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic.

No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.

Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with ramipril administration.

Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria.

In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

6.3 Clinical Laboratory Test Findings Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and a diuretic.

Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with a diuretic.

None of these increases required discontinuation of treatment.

Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis [ see Warnings and Precautions ( 5.3 ) ].

As ramipril decreases aldosterone secretion, elevation of serum potassium can occur.

Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient’s serum potassium frequently [ see Warnings and Precautions ( 5.8 ) ].

Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic.

No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.

Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with ramipril administration.

Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria.

In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.