Altace (Ramipril)

ALTACE®

Hoechst Marion Roussel

Ramipril

Angiotensin Converting Enzyme Inhibitor

Action And Clinical Pharmacology: Ramipril is an angiotensin-converting enzyme (ACE) inhibitor, which is used in the treatment of essential hypertension, and following acute myocardial infarction in stabilized patients with clinically confirmed heart failure.

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

Angiotensin-converting enzyme catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE activity leads to decreased levels of angiotensin II thereby resulting in decreased vasoconstriction and decreased aldosterone secretion. The latter decrease may result in a small increase in serum potassium (see Precautions). Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion result in increases in plasma renin activity.

ACE is identical to kininase II. Thus, ramipril may also block the degradation of the vasodepressor peptide bradykinin, which may contribute to its therapeutic effect.

Pharmacokinetics : Following oral administration, ramipril is rapidly absorbed with peak plasma concentrations occurring within 1 hour. The extent of absorption of ramipril is 50 to 60% and is not significantly altered by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced. Following absorption, ramipril is rapidly hydrolyzed in the liver to its active metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2 to 4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat is 56%.

Ramipril is almost completely metabolized to the active metabolite ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites are excreted in the urine, and about 40% are found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

Plasma 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 recommended dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28 and 44% respectively when 5 mg of oral ramipril was compared to 5 mg given i.v.

Plasma concentrations of ramiprilat decline in a triphasic manner. The initial rapid decline, which represents distribution of the drug, has a half-life of 2 to 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase has a half-life of 9 to 18 hours, and the terminal elimination phase has a prolonged half-life of >50 hours. After multiple daily doses of ramipril 5 to 10 mg, the half-life of ramiprilat concentrations was 13 to 17 hours, but was considerably prolonged at 2.5 mg (27 to 36 hours).

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

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. In patients with creatinine clearance
In patients with impaired liver function, plasma ramipril levels increased about 3-fold, although peak concentrations of ramiprilat in these patients were not different from those seen in patients with normal hepatic function.

A single-dose pharmacokinetic study conducted in a limited number of elderly patients indicated that peak ramiprilat levels and the AUC for ramiprilat are higher in older patients (see Precautions).

Pharmacodynamics: Administration of ramipril to patients with mild to moderate essential hypertension results in a reduction of both supine and standing blood pressure usually with little or no orthostatic change or change in heart rate. Symptomatic postural hypotension is infrequent, although this may occur in patients who are salt and/or volume-depleted (see Warnings).

In single-dose studies, doses of 5 to 20 mg of ramipril lowered blood pressure within 1 to 2 hours, with peak reductions achieved 3 to 6 hours after dosing. At recommended doses given once daily, antihypertensive effects have persisted over 24 hours.

The effectiveness of ramipril appears to be similar in the elderly (over 65 years of age) and younger adult patients given the same daily doses.

In studies comparing the same daily dose of ramipril given as a single morning dose or as a twice daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.

While the mechanism through which ramipril lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system, ramipril has an antihypertensive effect even in patients with low-renin hypertension.

The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in nonblacks.

The antihypertensive effect of ramipril and thiazide diuretics used concurrently is greater than that seen with either agent used alone.

Abrupt withdrawal of ramipril has not resulted in rapid increase in blood pressure.

Indications And Clinical Uses: Essential Hypertension: In the treatment of essential hypertension. It may be used alone or in association with thiazide diuretics.

Ramipril should normally be used in patients in whom treatment with a diuretic or a beta blocker was found ineffective or has been associated with unacceptable adverse effects.

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

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

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

Treatment Following Acute Myocardial Infarction: Ramipril is indicated following acute myocardial infarction in clinically stable patients with signs of left ventricular dysfunction to improve survival and reduce hospitalizations for heart failure.

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

General: In using ramipril consideration should be given to the risk of angioedema (see Warnings).

Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected ramipril should be discontinued as soon as possible (see Warnings, Pregnancy, and Information for the Patient).

Contra-Indications: Patients who are hypersensitive to this drug, or to any ingredient in the formulation, or in those patients who have a history of angioedema.

Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients with ACE inhibitors, including ramipril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, ramipril should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 to 0.5 mL of s.c. epinephrine solution 1:1 000) should be administered promptly (see Adverse Effects).

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in blacks than in nonblacks.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Hypotension: Symptomatic hypotension has occurred after administration of ramipril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see Adverse Effects). Because of the potential fall in blood pressure in these patients, therapy with ramipril should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of ramipril is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has been associated with oliguria, and/or progressive azotemia, and rarely, with acute renal failure and/or death.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an i.v. infusion of 0.9% sodium chloride. A transient hypotensive response may not be a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion in hypertensive patients. However, lower doses of ramipril and/or reduced concomitant diuretic therapy should be considered.

In patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of ramipril (see Adverse Effects, Treatment Following Acute Myocardial Infarction and Dosage, Treatment Following Acute Myocardial Infarction).

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Several cases of agranulocytosis, neutropenia or leukopenia have been reported in which a causal relationship to ramipril cannot be excluded. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ramipril should be discontinued as soon as possible.

In rare cases (probably less than one in every thousand pregnancies) in which no alternative to ACE inhibitor therapy will be found, the mother(s) should be apprised of the potential hazard(s) to their fetus(es). Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, ramipril should be discontinued unless it is considered life-saving for the mother. A non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until the fetus has sustained irreversible injury.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. 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 and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

Animal Data: No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. The doses used were: 10, 100 or 1 000 mg/kg in rats (2 500 times maximum human dose), 0.4, 1 or 2.5 mg/kg in rabbits (6.25 times maximum human dose), and 5, 50 or 500 mg/kg in cynomolgus monkeys (1 250 times maximum human dose). In rats, the highest dose caused reduced food intake in the dams, with consequent reduced birthweights of the pups and weight development during the lactation period. In rabbits, maternal effects were mortalities (high and middle dose) and reduced body weight. In monkeys, maternal effects were mortalities (high and middle dose), vomiting, and reduced weight gain.

Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of ramipril should include appropriate assessment of renal function.

Ramipril should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses (see Dosage). Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency.

Anaphylactoid Reactions during Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Anaphylactoid Reactions during Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Hyperkalemia and Potassium-Sparing Diuretics: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials treated with ramipril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy in any hypertensive patient. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (see Precautions, Drug Interactions).

Surgery/Anesthesia: In patients undergoing surgery or anesthesia with agents producing hypotension, ramipril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it may be corrected by volume repletion.

Aortic Stenosis: There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Patients with Impaired Liver Function: Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported with ramipril (see Adverse Effects). Should the patient receiving ramipril experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigations be carried out. Discontinuation of ramipril should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Ramipril should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Lactation: Ingestion of a single 10 mg oral dose of ramipril 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, ramipril should not be administered to nursing mothers.

Children: The safety and effectiveness of ramipril in children have not been established; therefore, use in this age group is not recommended.

Geriatrics: Although clinical experience has not identified differences in response between the elderly (>65 years) and younger patients, greater sensitivity of some older individuals cannot be ruled out (see Pharmacology, Pharmacokinetics).

Occupational Hazards: Ramipril may lower the state of patient alertness and/or reactivity, particularly at the start of treatment (see Adverse Effects).

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of ramipril, has been reported. Such possibility should be considered as part of the differential diagnosis of cough.

Drug Interactions: Concomitant Diuretic Therapy: Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of hypotensive effects after the first dose of ramipril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If it is not possible to discontinue the diuretic, the starting dose of ramipril should be reduced, and the patient should be closely observed for several hours following the initial dose and until blood pressure has stabilized (see Warnings and Dosage).

Agents Increasing Serum Potassium: Since ramipril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium, since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of ramipril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be further increased.

Antacids: In one open-label, randomized, cross-over single dose study in 24 male subjects, it was determined that the bioavailability of ramipril and the pharmacokinetic profile of ramiprilat were not affected by concomitant administration of the antacid, magnesium and aluminum hydroxides.

Digoxin: In one open-label study in 12 subjects, administered multiple doses of both ramipril and digoxin, no changes were found in serum levels of ramipril, ramiprilat and digoxin.

Warfarin: The coadministration of ramipril with warfarin did not alter the anticoagulant effects.

Acenocoumarol: In a multi-dose double-blind, placebo-controlled, pharmacodynamic interaction study with 14 patients with mild hypertension administered both ramipril and therapeutic doses of acenocoumarol, blood pressure, thrombotest time and coagulation factors were not significantly changed.

Nonsteroidal Anti-inflammatory Agents: The antihypertensive effects of ACE inhibitors may be reduced with concomitant administration of nonsteroidal anti-inflammatory agents (e.g., indomethacin).

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of ramipril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema, such as swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing. They should immediately stop taking ramipril and consult with their physician (see Warnings).

Hypotension: Patients should be cautioned to report lightheadedness, especially during the first few days of ramipril therapy. If actual syncope occurs, the patients should be told to discontinue the drug and consult with their physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure, patients should be advised to consult with their physician.

Agranulocytosis/Neutropenia: Patients should be told to report promptly to their physician any indication of infection (e.g., sore throat, fever) as this may be a sign of neutropenia (see Warnings and Adverse Effects).

Impaired Liver Function: Patients should be advised to return to their physician if they experience any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

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

Pregnancy: Since the use of ramipril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Adverse Reactions: Ramipril has been evaluated for safety in over 4 000 hypertensive patients. Almost 500 elderly patients have participated in controlled trials. Long-term safety has been assessed in almost 700 patients treated for 1 year or more. There was no increase in the incidence of adverse events in elderly patients given the same daily dose. The overall frequency of adverse events was not related to duration of therapy or total daily dose.

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

The most frequent adverse events occurring in these trials with ramipril monotherapy in hypertensive patients that were treated for at least 1 year (n=651) were: headache (15.1%); dizziness (3.7%); asthenia (3.7%); chest pain (2%); nausea (1.8%); peripheral edema (1.8%); somnolence (1.7%); impotence (1.5%); rash (1.4%); arthritis (1.1%); dyspnea (1.1%). Discontinuation of therapy due to clinical adverse events was required in 5 patients (0.8%).

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

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

Adverse events (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than one percent of stabilized patients with clinical signs of heart failure treated with ramipril following an acute myocardial infarction are shown in Tables I and II. The incidences represent the experiences from the AIRE (Acute Infarction Ramipril Efficacy) study. The follow-up time was between 6 and 48 months for this study (mean follow up = 15 months).

Isolated cases of death have been reported with the use of ramipril that appear to be related to hypotension (including first dose effects), but many of these are difficult to differentiate from progression of underlying disease (see Warnings, Hypotension).

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

Clinical Adverse Events by Body System: Clinical adverse events occurring in less than 1% of patients treated with ramipril in controlled clinical trials, or seen in postmarketing experience, are listed below by body system: Body as a Whole: anaphylactoid reactions, angioneurotic edema.

Cardiovascular: symptomatic hypotension, syncope, angina pectoris, arrhythmia, chest pain, palpitations, myocardial infarction, cerebrovascular disorders.

Respiratory: increased cough.

CNS: anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, polyneuritis, somnolence, tinnitus, tremor, vertigo, vision disturbances.

Dermatologic: apparent hypersensitivity reactions (with manifestations of urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, erythema multiforme, pemphigus, Stevens-Johnson syndrome.

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

Renal: increases in blood urea nitrogen (BUN) and serum creatinine.

Hematologic: leukopenia, eosinophilia, thrombocytopenia, pancytopenia and hemolytic anemia.

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

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur.

Clinical Laboratory Test Findings: increased creatinine; increases in blood urea nitrogen (BUN); decreases in hemoglobin or hematocrit; hyponatremia; elevations of liver enzymes, serum bilirubin, uric acid, blood glucose; proteinuria and significant increases in serum potassium.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Limited data are available regarding overdosage of ramipril in humans. Two cases of overdosage have been reported. In the case of an overdose with ramipril, the most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by i.v. volume expansion with normal saline. It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

Dosage And Administration: Essential Hypertension: Dosage of ramipril must be individualized. Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with ramipril may need to be adjusted.

Monotherapy: The recommended initial dosage of ramipril in patients not on diuretics is 2.5 mg once daily. Dosage should be adjusted according to blood pressure response, generally, at intervals of at least 2 weeks. The usual dose range is 2.5 to 10 mg once daily. A daily dose of 20 mg should not be exceeded.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not controlled with ramipril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of ramipril.

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

Renal Impairment: For patients with a creatinine clearance below 40 mL/min/1.73 m(serum creatinine above 2.5 mg/dL), the recommended initial dose is 1.25 mg ramipril once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg. In patients with severe renal impairment (creatinine clearance below 10 mL/min/1.73 m, the maximum dose of 2.5 mg ramipril should not be exceeded.

Treatment Following Acute Myocardial Infarction: Dosage of ramipril must be individualized. Initiation of therapy requires consideration of concomitant medication and baseline blood pressure and should be instituted under close medical supervision, usually in a hospital, 3 to 10 days following an acute myocardial infarction in hemodynamically stable patients with clinical signs of heart failure.

The recommended initial dosage of ramipril is 2.5 mg given twice a day (b.i.d.), 1 in the morning and 1 in the evening. If tolerated, and depending on the patient’s response, dosage may be increased by doubling at intervals of 1 to 3 days. The maximum daily dose of ramipril should not exceed 5 mg twice daily (b.i.d.).

After the initial dose of ramipril, the patient should be observed under medical supervision for at least 2 hours and until blood pressure has stabilized for at least an additional hour. If a patient becomes hypotensive at this dosage, it is recommended that the dosage be lowered to 1.25 mg b.i.d. following effective management of the hypotension (see Warnings, Hypotension).

Patients who have been fluid or salt depleted, or treated with diuretics are at an increased risk of hypotension (see Warnings, Hypotension). An excessive fall in blood pressure may occur particularly in the following: after the initial dose of ramipril; after every first increase of dose of ramipril; after the first dose of a concomitant diuretic and/or when increasing the dose of the concomitant diuretic. If appropriate, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension (see Precautions, Drug Interactions). Consideration should be given to reducing the initial dose to 1.25 mg of ramipril in these patients.

Renal Impairment: In patients with impaired renal function (creatinine clearance of 20 to 50 mL/min/1.73 mbody surface area), the initial recommended dosage is generally 1.25 mg of ramipril once daily. This dosage may be increased with caution up to 1.25 mg of ramipril twice daily, depending upon clinical response and tolerability.

Insufficient data are available concerning the use of ramipril following acute myocardial infarction in patients with heart failure and severe renal failure (see Pharmacology, Pharmacokinetics and Precautions, Renal Impairment).

Hepatic Impairment: Insufficient data are available concerning the use of ramipril following acute myocardial infarction in patients with heart failure and hepatic dysfunction. Dose reduction and careful monitoring of these patients is required (see Pharmacology, Pharmacokinetics and Precautions, Patients with Impaired Liver Function).

Availability And Storage: 1.25 mg: Each no. 4 hard gelatin capsule, with white opaque body, imprinted with “Altace” and yellow opaque cap, imprinted with “1.25”, contains: ramipril 1.25 mg. Nonmedicinal ingredients: gelatin NF, pregelatinized starch NF, titanium dioxide and yellow iron oxide.

2.5 mg: Each no. 4 hard gelatin capsule, with white opaque body, imprinted with “Altace” and orange opaque cap, imprinted with “2.5”, contains: ramipril 2.5 mg. Nonmedicinal ingredients: FD&C red No. 3, gelatin NF, pregelatinized starch NF, titanium dioxide and yellow iron oxide.

5 mg: Each no. 4 hard gelatin capsule, with white opaque body, imprinted with “Altace” and red opaque cap, imprinted with “5”, contains: ramipril 5 mg. Nonmedicinal ingredients: FD&C blue No. 2, FD&C red No. 3, gelatin NF, pregelatinized starch NF and titanium dioxide.

10 mg: Each No. 4 hard gelatin capsule, with white opaque body, imprinted with “Altace” and blue opaque cap, imprinted with “10”, contains: ramipril 10 mg. Nonmedicinal ingredients: black iron oxide, FD&C blue No. 2, FD&C red No. 3, gelatin NF, pregelatinized starch NF and titanium dioxide.

Cartons of 30 (2´15 blister-packed). Capsules of 2.5 mg or 5 mg are also available in white, high-density polyethylene (HDPE) bottles of 100 (for hospital use). Store in original container at room temperature, below 25°C and not beyond the date indicated on the container.

ALTACE® Hoechst Marion Roussel Ramipril Angiotensin Converting Enzyme Inhibitor

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