Ramipril Capsules (Altace Capsules)
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Ramipril Capsules (Altace Capsules)

ALTACE
(ramipril) Capsules

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ALTACE should be discontinued as soon as possible. See WARNINGS: Fetal/neonatal morbidity and mortality.

DRUG DESCRIPTION

Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°C and 112°C.

The CAS Registry Number is 87333-19-5. Ramipril's chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester; its structural formula is:

ALTACE (ramipril) structural formula illustration

Its empiric formula is C23H32N2O5, and its molecular weight is 416.5.

Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl angiotensin converting enzyme inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group.

ALTACE (ramipril) is supplied as hard shell capsules for oral administration containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril. The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.

What are the possible side effects of ramipril (Altace)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking ramipril and call your doctor at once if you have a serious side effect such as:

  • feeling like you might pass out;
  • high potassium level (slow heart rate, weak pulse, muscle weakness, tingly feeling;
  • dry mouth, thirst, confusion, swelling, and urinating less than usual or not at all;
  • pale skin, dark colored urine, easy bruising or bleeding;
  • jaundice...

Read All Potential Side Effects and See Pictures of Altace Capsules »

What are the precautions when taking ramipril capsules (Altace Capsules)?

Before taking ramipril, tell your doctor or pharmacist if you are allergic to it; or to other ACE inhibitors (such as benazepril); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: history of an allergic reaction which included swelling of the face/lips/tongue/throat (angioedema), blood filtering procedures (such as LDL apheresis, dialysis), high level of potassium in the blood, collagen vascular disease (such as lupus, scleroderma).

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are...

Read All Potential Precautions of Altace Capsules »

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

Altace (ramipril capsules) is 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. Altace (ramipril capsules) can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy).

Hypertension

ALTACE (ramipril capsules) is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. In using ALTACE (ramipril capsules) , consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that ALTACE does not have a similar risk. (See WARNINGS .)

In considering use of ALTACE (ramipril capsules) , it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients. (See WARNINGS , Angioedema.)

Heart Failure Post Myocardial Infarction

Ramipril is 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 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 PHARMACOLOGY , Heart Failure Post Myocardial Infarction for details and limitations of the survival trial.)

DOSAGE AND ADMINISTRATION

Blood pressure decreases associated with any dose of ALTACE (ramipril capsules) depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, the initial starting dose should be 1.25 mg once daily.

Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

ALTACE (ramipril capsules) should be given at an initial dose of 2.5 mg, once a day for 1 week, 5 mg, once a day for the next 3 weeks, and then increased as tolerated, to a maintenance dose of 10 mg, once a day. If the patient is hypertensive or recently post myocardial infarction, it can also be given as a divided dose.

Hypertension

The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Dosage should be adjusted according to the blood pressure response. The usual maintenance dosage range is 2.5 to 20 mg per day administered as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with ALTACE (ramipril capsules) alone, a diuretic can be added.

Heart Failure Post Myocardial Infarction

For the treatment of post-infarction patients who have shown signs of congestive failure, the recommended starting dose of ALTACE (ramipril capsules) is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily, and after one week at the starting dose, patients should then be titrated (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.

After the initial dose of ALTACE (ramipril capsules) , the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. (See WARNINGS and PRECAUTIONS: DRUG INTERACTIONS.) If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE (ramipril capsules) does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

The ALTACE (ramipril capsules) Capsule is usually swallowed whole. The ALTACE (ramipril capsules) Capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of apple sauce or mixed in 4 oz. (120 ml) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, the mixture should be consumed in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.

Concomitant administration of ALTACE (ramipril capsules) with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium. (See PRECAUTIONS.)

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of ALTACE (ramipril capsules) . To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with ALTACE. (See WARNINGS.) Then, if blood pressure is not controlled with ALTACE (ramipril capsules) alone, diuretic therapy should be resumed.

If the diuretic cannot be discontinued, an initial dose of 1.25 mg ALTACE (ramipril capsules) should be used to avoid excess hypotension.

Dosage Adjustment in Renal Impairment

In patients with creatinine clearance < 40 ml/min/1.73m2 (serum creatinine approximately > 2.5 mg/dl) doses only 25% of those normally used should be expected to induce full therapeutic levels of ramiprilat. (See CLINICAL PHARMACOLOGY.)

Hypertension: For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ALTACE (ramipril capsules) once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg.

Heart Failure Post Myocardial Infarction: For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ALTACE (ramipril capsules) once daily. The dose may be increased to 1.25 mg b.i.d. and up to a maximum dose of 2.5 mg b.i.d. depending upon clinical response and tolerability.

HOW SUPPLIED

ALTACE (ramipril capsules) is available in potencies of 1.25 mg, 2.5 mg, 5 mg, and 10 mg in hard gelatin capsules.

ALTACE (ramipril capsules) 1.25 mg capsules are supplied as yellow, hard gelatin capsules in bottles of 100 (NDC 61570-110-01).

ALTACE (ramipril capsules) 2.5 mg capsules are supplied as orange, hard gelatin capsules in bottles of 100 (NDC 61570-111-01), 500 (NDC 61570-111-05), Unit Dose packs of 100 (NDC 61570-111-56), and Bulk pack of 5000's (NDC 61570-111-50).

ALTACE (ramipril capsules) 5 mg capsules are supplied as red, hard gelatin capsules in bottles of 100 (NDC 61570-112-01), 500 (NDC 61570-112-05), Unit Dose packs of 100 (NDC 61570-112-56), and Bulk pack of 5000's (NDC 61570-112-50).

ALTACE (ramipril capsules) 10 mg capsules are supplied as Process Blue, hard gelatin capsules in bottles of 100 (NDC 61570-120-01), and 500 (NDC 61570-120-05).

Dispense in well-closed container with safety closure. Store at controlled room temperature (59° to 86°F).

Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620 (A wholly owned subsidiary of King Pharmaceuticals, Inc.) Manufactured by: King Pharmaceuticals, Inc., Bristol, TN 37620. Prescribing Information as of July 2008.

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Hypertension

ALTACE (ramipril capsules) has been evaluated for safety in over 4,000 patients with hypertension; of these, 1,230 patients were studied in US controlled trials, and 1,107 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 ALTACE (ramipril capsules) and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ALTACE (ramipril capsules) in US placebo-controlled trials were: headache (5.4%), "dizziness" (2.2%) and fatigue or asthenia (2.0%), but only the last was more common in ALTACE (ramipril capsules) 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 to 20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of US patients treated with ALTACE (ramipril capsules) . 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 US placebo-controlled trials in more than 1% of patients treated with ALTACE (ramipril capsules) , only asthenia (fatigue) was more common on Altace (ramipril capsules) than placebo (2% vs. 1%).

PATIENTS IN US PLACEBO CONTROLLED STUDIES

  ALTACE Placebo
(n=651) (n=286)
n % n %
Asthenia (Fatigue) 13 2 2 1

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.

Heart Failure Post Myocardial Infarction

Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than one percent of patients and more frequently on ramipril are shown below. The incidences represent the experiences from the AIRE study. The follow-up time was between 6 and 46 months for this study.

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

Adverse Event Ramipril Placebo
(n=1004) (n=982)
Hypotension 11 5
Cough Increased 8 4
Dizziness 4 3
Angina Pectoris 3 2
Nausea 2 1
Postural Hypotension 2 1
Syncope 2 1
Vomiting 2 0.5
Vertigo 2 0.7
Abnormal Kidney Function 1 0.5
Diarrhea 1 0.4

HOPE Study:

Safety data in the HOPE trial were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the AIRE trial. The rate of angioedema was the same as in previous clinical trials (see WARNINGS).

  RAMIPRIL PLACEBO
(N=4645) (N=4652)
% %
Discontinuation at any time 34 32
Permanent discontinuation 29 28
Reasons for stopping Cough 7 2
Hypotension or Dizziness 1.9 1.5
Angioedema 0.3 0.1

Other adverse experiences reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in postmarketing experience, include the following (in some, a causal relationship to drug use is uncertain):

Body As a Whole: Anaphylactoid reactions. (See WARNINGS.)

Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in US trials) (See WARNINGS and PRECAUTIONS ), syncope and palpitations.

Hematologic: Pancytopenia, hemolytic anemia and thrombocytopenia.

Renal: 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 ALTACE (ramipril capsules) , particularly when ALTACE (ramipril capsules) was given concomitantly with a diuretic. (See WARNINGS.) Acute renal failure.

Angioneurotic Edema: Angioneurotic edema has been reported in 0.3% of patients in US clinical trials. (See WARNINGS.)

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.

Fetal/Neonatal Morbidity and Mortality. See WARNINGS : Fetal/Neonatal Morbidity and Mortality .

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

Post-Marketing Experience: In addition to adverse events reported from clinical trials, there have been rare reports of hypoglycemia reported during ALTACE (ramipril capsules) therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.

Clinical Laboratory Test Findings

Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE (ramipril capsules) alone, and in 1.5% of patients receiving ALTACE (ramipril capsules) and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ALTACE (ramipril capsules) alone and in 3% of patients receiving ALTACE (ramipril capsules) 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.) Since ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Potassium supplements and potassium-sparing diuretics should be given with caution, and the patient's serum potassium should be monitored frequently. (See WARNINGS and PRECAUTIONS.)

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 ALTACE (ramipril capsules) alone and in 1.5% of patients receiving ALTACE (ramipril capsules) 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 ALTACE (ramipril capsules) administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leukopenia, 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.

Read the Altace Capsules (ramipril capsules) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

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

With nonsteroidal anti-inflammatory agents: Rarely, concomitant treatment with ACE inhibitors and nonsteroidal anti-inflammatory agents have been associated with worsening of renal failure and an increase in serum potassium.

With 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 ALTACE (ramipril capsules) . The possibility of hypotensive effects with ALTACE (ramipril capsules) can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ALTACE (ramipril capsules) . If this is not possible, the starting dose should be reduced. (See DOSAGE AND ADMINISTRATION.)

With potassium supplements and potassium-sparing diuretics: ALTACE (ramipril capsules) can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently.

With 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 coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Other: Neither ALTACE (ramipril capsules) nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of ALTACE (ramipril capsules) and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of ALTACE (ramipril capsules) and warfarin did not adversely affect the anticoagulant effects of the latter drug. Additionally, co-administration of ALTACE (ramipril capsules) with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the subjects' state of anti-coagulation.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS : Fetal/Neonatal Morbidity and Mortality .

Nursing Mothers

Ingestion of single 10 mg oral dose of ALTACE resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from single doses, women receiving ALTACE (ramipril capsules) should not breast feed.

Geriatric Use

Of the total number of patients who received ramipril in US clinical studies of ALTACE (ramipril capsules) 11.0% were 65 and over while 0.2% were 75 and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration time curve (AUC) for ramiprilat are higher in older patients.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given a single dose of ramipril.

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ALTACE (ramipril capsules) ) may be subject to a variety of adverse reactions, some of them serious.

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. (See also CONTRAINDICATIONS.)

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin converting enzyme inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ALTACE (ramipril capsules) should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1,000 (0.3 ml to 0.5 ml) should be promptly administered. (See ADVERSE REACTIONS .)

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. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

In a large U.S. postmarketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) of black patients and in 8/8680 (0.09%) of white patients. These rates were not different statistically.

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.

Hypotension

ALTACE (ramipril capsules) can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, ramipril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with ALTACE (ramipril capsules) .

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, ALTACE (ramipril capsules) therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of ramipril or diuretic is increased.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of physiological saline. ALTACE (ramipril capsules) treatment usually can be continued following restoration of blood pressure and volume.

Hepatic Failure

Rarely, ACE inhibitors, including Altace (ramipril capsules) , 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.

Neutropenia/Agranulocytosis

As with other ACE inhibitors, rarely, a mild - in isolated cases severe - reduction in the red blood cell count and hemoglobin content, white blood cell or platelet count may develop. 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. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

Fetal/Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors 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; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been confirmed.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, ALTACE (ramipril capsules) should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories 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 means of reversing hypotension and/or substituting for disordered renal function. ALTACE (ramipril capsules) which crosses the placenta can be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.

No teratogenic effects of ALTACE (ramipril capsules) were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

PRECAUTIONS

Impaired Renal Function: 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 angiotensin converting enzyme inhibitors, including ALTACE (ramipril capsules) , may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/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 angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of ALTACE (ramipril capsules) and/or diuretic therapy. In such patients renal function should be monitored 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 ALTACE (ramipril capsules) has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of ALTACE (ramipril capsules) and/or discontinuation of the diuretic may be required.

Evaluation of the hypertensive patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)

Hyperkalemia: In clinical trials, hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving ALTACE (ramipril). In most cases, these were isolated values, which resolved despite continued therapy. None of these patients was discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with ALTACE. (See DRUG INTERACTIONS.)

Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Impaired Liver Function: Since 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. However, since the renin-angiotensin system may be activated in patients with severe liver cirrhosis and/or ascites, particular caution should be exercised in treating these patients.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Single oral doses in rats and mice of 10-11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension.

Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be usefully removed from the body by hemodialysis.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.

CONTRAINDICATIONS

ALTACE (ramipril capsules) is contraindicated in patients who are hypersensitive to this product or any other angiotensin converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Ramipril and ramiprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that 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 results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with ALTACE (ramipril capsules) alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ALTACE (ramipril capsules) and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater, and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/ L or greater. (See PRECAUTIONS .) Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ALTACE (ramipril capsules) remains to be elucidated.

While the mechanism through which ALTACE (ramipril capsules) lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, ALTACE (ramipril capsules) has an antihypertensive effect even in patients with low-renin hypertension. Although ALTACE (ramipril capsules) was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non-black patients.

Pharmacokinetics and Metabolism

Following oral administration of ALTACE, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50-60% and is not significantly influenced by the presence of food in the GI tract, although the rate of absorption is reduced.

In a trial in which subjects received ALTACE (ramipril capsules) capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in apple sauce, serum ramiprilat levels were essentially unrelated to the use or nonuse of the concomitant liquid or food.

Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid 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 about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 to 10ug/ml. Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites is eliminated 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, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5-20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously. Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2—4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9-18 hours. The terminal elimination phase has a prolonged half-life ( > 50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13-17 hours.

After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE (ramipril capsules) , especially at low doses (2.5 mg), but the difference is clinically insignificant.

In patients with creatinine clearance less than 40 ml/min/1.73m2, peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3-4 times as large as it is in patients with normal renal function who receive similar doses.

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance less than 40 ml/min/1.73m2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations. (See DOSAGE AND ADMINISTRATION .)

In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.

Pharmacodynamics

Single doses of ramipril of 2.5-20 mg produce approximately 60-80% inhibition of ACE activity 4 hours after dosing with approximately 40-60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.

Pharmacodynamics and Clinical Effects

Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

The Heart Outcomes Prevention Evaluation study (HOPE study) was a large, multi-center, randomized, placebo controlled, 2x2 factorial design, double-blind study conducted in 9,541 patients (4,645 on ALTACE (ramipril capsules) ) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction ( < 0.40). This study was designed to examine the long-term (mean of five years) effects of ALTACE (ramipril capsules) (10 mg orally once a day) on the combined endpoint of myocardial infarction, stroke or death from cardiovascular causes.

The HOPE study results showed that ALTACE (ramipril capsules) (10 mg/day) significantly reduced the rate of myocardial infarction, stroke or death from cardiovascular causes (651/4645 vs. 826/4652, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint.

Outcome ALTACE Placebo Relative Risk
(N=4645) (N=4652) (95% CI)
  no. (%) P value
Combined End-Point
   (MI, stroke, or death from CV cause) 651 (14.0%) 826 (17.8%) 0.78 (0.70-0.86), P=0.0001
Component End-Point
   Death from Cardiovascular Causes 282 (6.1%) 377 (8.1%) 0.74 (0.64-0.87), P=0.0002
   Myocardial infarction 459 (9.9%) 570 (12.3%) 0.80(0.70-0.90), P=0.0003
   Stroke 156 (3.4%) 226 (4.9%) 0.68 (0.56-0.84), P=0.0002
Overall Mortality
   (Death from any Cause) 482 (10.4%) 569 (12.2%) 0.84 (0.75-0.95), P=0.005

This effect was evident after about one year of treatment.

Kaplan-Meier Estimates of the composite outcome of MI, Stroke, or Death from CV causes in the Ramipril Group and the Placebo Group - illustration

Figure 1: Kaplan-Meier Estimates of the composite outcome of MI, Stroke, or Death from CV causes in the Ramipril Group and the Placebo Group. The relative risk of the composite outcomes in the Ramipril Group as compared with the Placebo Group was 0.78%.
(95% confidence interval, 0.70-0.86).

Ramipril was effective in different demographic subgroups, (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not ramipril was equally effective in ethnic subgroups.

This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of ramipril on the combined endpoint and its components were similar in diabetics (n=3,577) to those in the overall study population.

Outcome ALTACE Placebo Relative Risk Reduction
(N=1808) (N=1769)  
  no. (%) (95% CI)
Combined End-Point
   (MI, stroke, or death from CV cause) 277 (15.3%) 351 (19.8%) 0.25 (0.12-0.36), P=0.0004
Component End-Point
   Death from Cardiovascular Causes 112 (6.2%) 172 (9.7%) 0.37 (0.21-0.51), P=0.0001
   Myocardial infarction 185 (10.2%) 229 (12.9%) 0.22(0.06-0.36), P=0.01
   Stroke 76 (4.2%) 108 (6.1%) 0.33 (0.10-0.50), P=0.007

The Beneficial Effect of Treatment with Ramipril on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups - illustration

Figure 2: The Beneficial Effect of Treatment with Ramipril on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups. Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.

The benefits of Altace (ramipril capsules) were observed among patients who were taking aspirin or other anti-platelet agents, beta-blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.

Hypertension

Administration of ALTACE (ramipril capsules) to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. (See WARNINGS .) Use of ALTACE (ramipril capsules) in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone.

In single-dose studies, doses of 5-20 mg of ALTACE (ramipril capsules) lowered blood pressure within 1-2 hours, with peak reductions achieved 3-6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4-12 weeks) controlled studies, once-daily doses of 2.5-10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mm Hg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50-60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients the antihypertensive effect with once-daily dosing is not adequately maintained. (See DOSAGE AND ADMINISTRATION.)

In most trials, the antihypertensive effect of ALTACE (ramipril capsules) increased during the first several weeks of repeated measurements. The antihypertensive effect of ALTACE (ramipril capsules) has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of ALTACE (ramipril capsules) has not resulted in a rapid increase in blood pressure.

ALTACE (ramipril capsules) has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. It was approximately as effective as other ACE inhibitors and as atenolol. In both caucasians and blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril.

Except for thiazides, no formal interaction studies of ramipril with other antihypertensive agents have been carried out. Limited experience in controlled and uncontrolled trials combining ramipril with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.

ALTACE (ramipril capsules) was less effective in blacks than in caucasians. The effectiveness of ALTACE (ramipril capsules) was not influenced by age, sex, or weight. In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.

Heart Failure Post Myocardial Infarction

ALTACE (ramipril capsules) was studied in the Acute Infarction Ramipril Efficacy (AIRE) trial. This was a multinational (mainly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing ALTACE (ramipril capsules) to placebo in stable patients, 2-9 days after an acute myocardial infarction (MI), who had shown clinical signs of congestive heart failure (CHF) at any time after the MI. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days. Patients randomized to ramipril treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to ramipril) of 5 mg twice daily. Patients were then followed for an average of 15 months (range 6-46).

The use of ALTACE (ramipril capsules) was associated with a 27% reduction (p=0.002), in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of CHF-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of ALTACE (ramipril capsules) therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on, and not on, various concomitant medications; at the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors during pregnancy. These patients should be asked to report pregnancies to their physicians as soon as possible.

Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported. Patients should be told that if syncope occurs, ALTACE (ramipril capsules) should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors during pregnancy. These patients should be asked to report pregnancies to their physicians as soon as possible.

Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported. Patients should be told that if syncope occurs, ALTACE (ramipril capsules) should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

Last reviewed on RxList: 6/12/2009
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Altace Capsules Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

RAMIPRIL - ORAL

(RAM-ih-prill)

COMMON BRAND NAME(S): Altace

WARNING: This drug can cause serious (possibly fatal) harm to an unborn baby if used during pregnancy. Therefore, it is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss the use of reliable forms of birth control while taking this medication. If you are planning pregnancy, become pregnant, or think you may be pregnant, contact your doctor immediately.

USES: Ramipril is used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Ramipril is also used to improve survival after a heart attack. It may also be used in high risk patients (such as patients with heart disease/diabetes) to help prevent heart attacks and strokes.

Ramipril is an ACE inhibitor and works by relaxing blood vessels so that blood can flow more easily.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat heart failure or to help protect the kidneys from harm due to diabetes.

HOW TO USE: Take this medication by mouth with or without food as directed by your doctor, usually once or twice daily.

If you are taking the capsule form of ramipril, swallow it whole. If you have difficulty swallowing the capsule, the capsule may be opened and the contents sprinkled onto cool applesauce (about 4 ounces) or mixed in half a glass of water or apple juice (4 ounces/120 milliliters). Swallow or drink the whole mixture.

The dosage is based on your medical condition and response to treatment.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time(s) each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick.

For the treatment of high blood pressure, it may take several weeks before you get the full benefit of this medication. Tell your doctor if your condition does not improve or if it worsens (such as your blood pressure readings remain high or increase).

Disclaimer

Altace Capsules Consumer (continued)

SIDE EFFECTS: Dizziness, lightheadedness, or tiredness may occur as your body adjusts to the medication. Dry cough may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if any of these unlikely but serious side effects occur: fainting, muscle weakness, signs of infection (such as fever, chills, persistent sore throat), change in the amount of urine.

This drug may rarely cause serious (possibly fatal) liver problems. Tell your doctor right away if you notice any of the following rare but serious side effects: yellowing eyes/skin, dark urine, severe stomach/abdominal pain, persistent nausea/vomiting.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Altace Capsules (ramipril capsules) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking ramipril, tell your doctor or pharmacist if you are allergic to it; or to other ACE inhibitors (such as benazepril); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: history of an allergic reaction which included swelling of the face/lips/tongue/throat (angioedema), blood filtering procedures (such as LDL apheresis, dialysis), high level of potassium in the blood, collagen vascular disease (such as lupus, scleroderma).

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Too much sweating, diarrhea, or vomiting may cause loss of too much body water (dehydration) and increase your risk of lightheadedness. Report prolonged diarrhea or vomiting to your doctor. Be sure to drink enough fluids to prevent dehydration unless your doctor directs you otherwise.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This product may increase your potassium levels. Before using potassium supplements or salt substitutes that contain potassium, consult your doctor or pharmacist.

Older adults may be more sensitive to the effects of this product, especially dizziness.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. Consult your doctor for more details. (See also Warning section.)

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Altace Capsules Consumer (continued)

DRUG INTERACTIONS: See also Precautions section.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: aliskiren, lithium, drugs that may increase your potassium level (including birth control products that contain drospirenone), telmisartan.

Check the labels on all your medicines (such as cough-and-cold products, diet aids, or NSAIDs such as ibuprofen, naproxen) because they may contain ingredients that could increase your blood pressure or worsen your heart failure. Ask your pharmacist for more details.

A very serious reaction may occur if you are getting injections for bee/wasp sting allergy (desensitization) and are also taking ramipril. Make sure all your doctors know which medicines you are using.

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe dizziness, fainting.

NOTES: Do not share this medication with others.

Lifestyle changes such as stress reduction programs, exercise and dietary changes may increase the effectiveness of this medicine. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

Laboratory and/or medical tests (such as kidney function, potassium levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Check your blood pressure regularly while taking this medication. Learn how to monitor your own blood pressure at home, and share the results with your doctor.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature away from light and moisture. If you are taking the capsule form of ramipril and have opened the capsule and mixed the contents with food or liquid, then the mixture can be kept at room temperature for up to 24 hours or refrigerated for up to 48 hours. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised April 2012. Copyright(c) 2012 First Databank, Inc.

Altace Capsules Patient Information Including Side Effects

Brand Names: Altace

Generic Name: ramipril (Pronunciation: RAM i pril)

What is ramipril (Altace Capsules)?

Ramipril is in a group of drugs called ACE inhibitors. ACE stands for angiotensin converting enzyme.

Ramipril is used to treat high blood pressure (hypertension) or congestive heart failure, and to improve survival after a heart attack.

Ramipril may also be used for purposes not listed in this medication guide.

Altace 1.25 mg

yellow, imprinted with ALTACE 1.25 mg, MP

Altace 10 mg

blue, imprinted with ALTACE 10 MG, HOECHST

Altace 2.5 mg

orange, imprinted with ALTACE 2.5 mg, MP

Altace 5 mg

red, imprinted with ALTACE 5 mg

Ramipril 1.25 mg-APO

white/yellow, imprinted with APO, 1.25

Ramipril 1.25 mg-COB

white/yellow, imprinted with LOGO, RP 1.25

Ramipril 1.25 mg-ROX

yellow, imprinted with 54 328

Ramipril 10 mg-APO

blue/white, imprinted with APO, 10

Ramipril 10 mg-COB

blue/white, imprinted with LOGO, RP 10

Ramipril 10 mg-ROX

blue, imprinted with 54 602

Ramipril 10 mg-TEV

blue, imprinted with 93 7438

Ramipril 2.5 mg-APO

red/white, imprinted with APO, 2.5

Ramipril 2.5 mg-COB

orange/white, imprinted with LOGO, RP 2.5

Ramipril 2.5 mg-ROX

orange, imprinted with 54 794

Ramipril 2.5 mg-TEV

yellow, imprinted with 93 7436

Ramipril 5 mg-APO

red/white, imprinted with APO, 5

Ramipril 5 mg-COB

red/white, imprinted with LOGO, RP 5

Ramipril 5 mg-ROX

orange, imprinted with 54 145

Ramipril 5 mg-TEV

pink, imprinted with 93 7437

What are the possible side effects of ramipril (Altace Capsules)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking ramipril and call your doctor at once if you have a serious side effect such as:

  • feeling like you might pass out;
  • high potassium level (slow heart rate, weak pulse, muscle weakness, tingly feeling;
  • dry mouth, thirst, confusion, swelling, and urinating less than usual or not at all;
  • pale skin, dark colored urine, easy bruising or bleeding;
  • jaundice (yellowing of the skin or eyes); or
  • fever, chills, body aches, flu symptoms, sores in your mouth and throat.

Less serious side effects may include:

  • cough;
  • tired feeling, headache;
  • dizziness, spinning sensation; or
  • nausea, vomiting.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Altace Capsules (ramipril capsules) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about ramipril (Altace Capsules)?

Avoid drinking alcohol. It can further lower your blood pressure and may increase some of the side effects of ramipril.

Do not use salt substitutes or potassium supplements while taking ramipril, unless your doctor has told you to.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, dehydration, a low salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Your blood pressure will need to be checked often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.

If you need surgery, tell the surgeon ahead of time that you are using ramipril. You may need to stop using the medicine for a short time.

If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms.

Side Effects Centers

Altace Capsules Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking ramipril (Altace Capsules)?

You should not use this medication if you are allergic to ramipril or to any other ACE inhibitor, such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), or trandolapril (Mavik).

To make sure you can safely take ramipril, tell your doctor if you have any of these other conditions:

  • kidney disease (or if you are on dialysis);
  • liver disease;
  • diabetes;
  • a connective tissue disease such as Marfan syndrome, Sjogren's syndrome, lupus, scleroderma, or rheumatoid arthritis;
  • if you are also taking telmisartan (Micardis); or
  • if you have ever had a severe allergic reaction.

FDA pregnancy category D. Do not use ramipril if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Ramipril can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control while taking ramipril.

Ramipril can pass into breast milk and may harm a nursing baby. You should not breast-feed while taking ramipril.

How should I take ramipril (Altace Capsules)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Ramipril can be taken with or without food.

Swallow the ramipril tablet whole.

You may open the ramipril capsule and sprinkle the medicine into a half-cup (4 ounces) of water, apple juice, or applesauce to make swallowing easier. Swallow without chewing. You may store the mixture for up to 24 hours at room temperature, or up to 48 hours in a refrigerator.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, dehydration, a low salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

To be sure this medication is helping your condition, your blood pressure will need to be checked often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.

If you need surgery, tell the surgeon ahead of time that you are using ramipril. You may need to stop using the medicine for a short time.

If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms.

Store at room temperature away from moisture and heat.

Side Effects Centers

Altace Capsules Patient Information including If I Miss a Dose

What happens if I miss a dose (Altace Capsules)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Altace Capsules)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include feeling extremely dizzy or light-headed, or fainting.

What should I avoid while taking ramipril (Altace Capsules)?

Avoid drinking alcohol. It can further lower your blood pressure and may increase some of the side effects of ramipril.

Do not use salt substitutes or potassium supplements while taking ramipril, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

What other drugs will affect ramipril (Altace Capsules)?

Tell your doctor about all other medicines you use, especially:

  • a diuretic (water pill);
  • gold injections to treat arthritis;
  • lithium (Lithobid, Eskalith);
  • a potassium supplement such as K-Dur, Klor-Con;
  • salt substitutes that contain potassium; or
  • aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Cataflam, Voltaren), indomethacin (Indocin), meloxicam (Mobic), and others.

This list is not complete and other drugs may interact with ramipril. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about ramipril.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 12.01. Revision date: 3/14/2011.

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