Ramipril: uses, appearance and warnings

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 are 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 is supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril. Ramipril Capsules USP, 1.25 mg are yellow/yellow size ‘4’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘05’ on yellow body with black edible ink filled with white to almost white powder. Ramipril Capsules USP, 2.5 mg are orange/orange size ‘4’ hard gelatin capsules imprinted with ‘D’ on orange cap and ‘06’ on orange body with black edible ink filled with white to almost white powder. Ramipril Capsules USP, 5 mg are red/red size ‘4’ hard gelatin capsules imprinted with ‘D’ on red cap and ‘07’ on red body with black edible ink filled with white to almost white powder. Ramipril Capsules USP, 10 mg are blue/blue size ‘4’ hard gelatin capsules imprinted with ‘D’ on blue cap and ‘08’ on blue body with black edible ink filled with white to almost white powder. Capsule: 1.25 mg, 2.5 mg, 5 mg, and 10 mg (3)

Ramipril Capsules USP, 1.25 mg are yellow/yellow size ‘4’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘05’ on yellow body with black edible ink filled with white to almost white powder. Bottles of 100 NDC 68001-428-00 Ramipril Capsules USP, 2.5 mg are orange/orange size ‘4’ hard gelatin capsules imprinted with ‘D’ on orange cap and ‘06’ on orange body with black edible ink filled with white to almost white powder. Bottles of 100 NDC 68001-429-00 Ramipril Capsules USP, 5 mg are red/red size ‘4’ hard gelatin capsules imprinted with ‘D’ on red cap and ‘07’ on red body with black edible ink filled with white to almost white powder. Bottles of 100 NDC 68001-430-00 Bottles of 500 NDC 68001-430-03 Ramipril Capsules USP, 10 mg are blue/blue size ‘4’ hard gelatin capsules imprinted with ‘D’ on blue cap and ‘08’ on blue body with black edible ink filled with white to almost white powder. Bottles of 100 NDC 68001-431-00 Bottles of 500 NDC 68001-431-03 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in well-closed container with safety closure.

Ramipril capsules are contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor). Ramipril capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer ramipril capsules within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Warnings and Precautions (5.1) ] . Do not co-administer ramipril capsules with aliskiren: • in patients with diabetes Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema (4) . Ramipril capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer ramipril capsules within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor ( 4 ). Do not co-administer aliskiren with ramipril capsules in patients with diabetes (4) .

Angioedema, increased risk in patients with a prior history (5.1) Hypotension and hyperkalemia (5.5, 5.8) Renal impairment: monitor renal function during therapy (5.3) Avoid concomitant use of an ACE inhibitor and angiotensin blocker (5.7) Rare cholestatic jaundice and hepatic failure (5.2) Rare neutropenia and agranulocytosis (5.4) 5.1 Anaphylactoid and Possibly Related Reactions Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including ramipril) may be subject to a variety of adverse reactions, some of them serious. Angioedema Angioedema may occur at any time during treatment with ACE inhibitors including ramipril. Head and Neck Angioedema Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. A+ngioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with ramipril and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly [see Adverse Reactions (6) ] . In considering the use of ramipril, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients. In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.2%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different statistically. Patients taking concomitant mammalian target of rapamycin (mTOR) inhibitor (e.g., temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema [see Drug Interactions (7.7) ]. Intestinal Angioedema 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 there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid Reactions During Membrane Exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. 5.2 Hepatic Failure and Impaired Liver Function 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. Discontinue ramipril if patient develops jaundice or marked elevations of hepatic enzymes. As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. 5.3 Renal Impairment As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ramipril, may be associated with oliguria or progressive azotemia and rarely with acute renal failure or death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon discontinuation of ramipril and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when ramipril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ramipril and/or discontinuation of the diuretic may be required. 5.4 Neutropenia and Agranulocytosis In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function. …

The most common adverse reactions in patients with hypertension included headache, dizziness, fatigue, and cough (6.1) .To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or 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. …

Diuretics: Possibility of excessive hypotension ( 7.1 ). Lithium: Use with caution (7.4) . Gold: Nitritoid reactions have been reported ( 7.5 ). NSAIDs use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.6 ). mTOR inhibitor or neprilysin inhibitor use may increase angioedema risk ( 7.7 ) 7.1 Diuretics Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, reduce the starting dose [see Dosage and Administration (2) ] . …