Altace

Since ALTACE 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. (See also Non-steroidal Anti-inflammatory Agents and Acetylsalicylic Acid.)

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 ALTACE can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ALTACE. If it is not possible to discontinue the diuretic, the starting dose of ALTACE 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 Precautions and Dosage and Administration). Regular monitoring of serum sodium is recommended in patients undergoing concurrent diuretic therapy.

The antihypertensive effects of ACE inhibitors may be reduced with concomitant administration of non-steroidal anti-inflammatory agents (e.g. indomethacin). Concomitant treatment of ACE inhibitors and Non-Steroidal Anti-Inflammatory drugs may lead to an increased risk of worsening of renal function and an increase in serum potassium. (See also Agents Increasing Serum Potassium.)

Potentiation of the antihypertensive effect is to be anticipated.

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.

The antihypertensive effect of ALTACE is augmented by antihypertensive agents that cause renin release (e.g. diuretics).

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.

The co-administration of ALTACE with warfarin did not alter the anticoagulant effects.

Rise in serum potassium concentration possible.

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

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.

These may reduce the antihypertensive effect of ALTACE. Particularly close blood pressure monitoring is recommended.

Insufficient data is 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 Actions and Clinical Pharmacology, Pharmacokinetics and Warnings and Precautions, Hepatic/Biliary/Pancreatic).

Dosage of ALTACE 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, three to ten days following an acute myocardial infarction in haemodynamically stable patients with clinical signs of heart failure.

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

After the initial dose of ALTACE, 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. If a patient becomes hypotensive at this dosage, it is recommended that the dosage be lowered to 1.25 mg b.i.d. following effective management of the hypotension (see Warnings and Precautions, Cardiovascular, Hypotension).

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

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

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

Recommended initial dose: 2.5 mg of ALTACE once daily. Depending on the tolerability, the dose is gradually increased. It is recommended to double the dose after one week of treatment and—after another three weeks—to increase it to 10 mg. Usual maintenance dose: 10 mg of ALTACE daily (see Action and Clinical Pharmacology and Warnings and Precautions).

Dosage recommendations for special risk groups such as patients with renal or hepatic impairment, or at an increased risk of hypotension (fluid or salt depletion, treated with diuretics) are to be followed as previously described (see Warnings and Precautions).

Dosage of ALTACE 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 ALTACE may need to be adjusted.

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

The recommended initial dosage of ALTACE 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 two 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 ALTACE alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of ALTACE.

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

hepatic failure, cholestatic jaundice, hepatitis, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), increased levels of pancreatic enzymes, anorexia, constipation, diarrhea, digestive disturbances, dry mouth, dyspepsia, dysphagia, gastroenteritis, nausea, increased salivation, smell and taste disturbance, vomiting, abdominal discomfort. In isolated cases liver damage (including acute liver failure) may occur.

Rarely, ACE inhibitors, including ALTACE, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.

Increased creatinine; increases in blood urea nitrogen (BUN); decreases in red blood cell count, hemoglobin or hematocrit; hyponatraemia; elevations of liver enzymes, serum bilirubin, uric acid, blood glucose; proteinuria and significant increases in serum potassium.

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

Clinical adverse events occurring in less than 1% of patients treated with ALTACE in controlled clinical trials, or seen in post-marketing experience, are listed below by body system:

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

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

anaphylactoid reactions, angioedema.

increased cough, nasal congestion, sinusitis, bronchitis, and bronchospasm.

agranulocytosis, leucopenia, eosinophilia, thrombocytopenia, pancytopaenia, bone marrow depression and hemolytic anemia (see Warnings and Precautions, Hematologic, Neutropenia/Agranulocytosis).

ALTACE has been evaluated for safety in over 4000 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 placebo-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=1244), angioedema occurred in 0.1% patients treated with ramipril and a diuretic.

The most frequent adverse events occurring in these trials with ALTACE monotherapy in hypertensive patients that were treated for at least one year (n=651) were: headache (15.1%); dizziness (3.7%); asthenia (3.7%); chest pain (2.0%); nausea (1.8%); peripheral edema (1.8%); somnolence (1.7%); impotence (1.5%); rash (1.4%); arthritis (1.1%); dyspnea (1.1%). Discontinuation of therapy due to clinical 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 ALTACE patients, with about 4% of these patients requiring discontinuation of treatment. Approximately 1% of patients treated with ALTACE monotherapy in North American controlled clinical trials (n=972) have required discontinuation because of cough.

anxiety, amnesia, confusion, convulsions, depression, hearing loss, insomnia, sleep disturbances, nervousness, neuralgia, neuropathy, paresthesia, polyneuritis, somnolence, tinnitus, tremor, vertigo, vision disturbances, disorders of balance, lightheadness, restlessness, precipitation or intensification of Raynaud’s phenomenon.

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

The long-term safety of ramipril, as monotherapy was assessed in patients with hypertension. The most commonly reported serious adverse reactions were hypotension (0.1%); myocardial infarction (0.3%); cerebrovascular accident (0.1%); edema (0.2%); syncope (0.1%). Angioedema occurred in 0.1% patients treated with ramipril and a diuretic.

The most frequent adverse events occurring in these trials were: headache (15.1%); dizziness (3.7%); asthenia (3.7%); chest pain (2.0%); nausea (1.8%); peripheral edema (1.8%); somnolence (1.7%); impotence (1.5%); rash (1.4%); arthritis (1.1%); dyspnea (1.1%). Discontinuation of therapy due to clinical adverse events was required in 0.8% of patients treated with ALTACE. Approximately 1% of patients in North American controlled clinical trials have required discontinuation because of cough.

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

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

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

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

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

symptomatic hypotension, flushing, syncope, angina pectoris, arrhythmia, chest pain, palpitations, tachycardia, myocardial infarction, cerebrovascular disorders (including ischaemic stroke), disturbed orthostatic regulation, exacerbation of perfusion disturbances due to vascular stenoses.

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 and Precautions, Cardiovascular, Hypotension).

Discontinuation of therapy due to adverse reactions was required in 368/1004 post-AMI patients taking ramipril (36.7%), compared to 401/982 patients receiving placebo (40.8%).

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

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

Primary detoxification by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the first 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

No experience is available concerning the efficacy of forced diuresis, alteration in urine pH, haemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or haemofiltration is nevertheless considered, see also Warnings and Precautions, Immune, Anaphylactoid Reactions During Membrane Exposure.

Each hard gelatin capsule size no. 4, with white opaque body, imprinted with “Altace” and red opaque cap, imprinted with “5”, contains: ramipril 5 mg. Nonmedicinal ingredients: pregelatinized starch; capsule: FD&C Blue No. 2, FD&C Red No. 3, gelatin and titanium dioxide. Cartons of 30 (2×15 blister-packed capsules). White, high-density polyethylene (HDPE) bottles of 100 and 500.

Each hard gelatin capsule size no. 4, with white opaque body, imprinted with “Altace” and orange opaque cap, imprinted with “2.5”, contains: ramipril 2.5 mg. Nonmedicinal ingredients: pregelatinized starch; capsule: FD&C Red No. 3, gelatin, titanium dioxide and yellow iron oxide. Cartons of 30 (2×15 blister-packed capsules). White, high-density polyethylene (HDPE) bottles of 100 and 500.

Each hard gelatin capsule size no. 3, with grey opaque body, imprinted with “Altace” and powder blue opaque cap, imprinted with “15”, contains: ramipril 15 mg. Nonmedicinal ingredients: pregelatinized starch; capsule: black iron oxide, D&C Red No. 28, FD&C Blue No. 1, gelatin and titanium dioxide. Cartons of 30 (2×15 blister-packed capsules). White, high-density polyethylene (HDPE) bottles of 100 and 500.

Each hard gelatin capsule size no. 4, with white opaque body, imprinted with “Altace” and yellow opaque cap, imprinted with “1.25”, contains: ramipril 1.25 mg. Nonmedicinal ingredients: pregelatinized starch; capsule: gelatin, titanium dioxide and yellow iron oxide. Cartons of 30 (2×15 blister-packed capsules). White, high-density polyethylene (HDPE) bottles of 100.

Each hard gelatin capsule size no. 4, with white opaque body, imprinted with “Altace” and blue opaque cap, imprinted with “10”, contains: ramipril 10 mg. Nonmedicinal ingredients: pregelatinized starch; capsule: black iron oxide, FD&C Blue No. 2, FD&C Red No. 3, gelatin and titanium dioxide. Cartons of 30 (2×15 blister-packed capsules). White, high-density polyethylene (HDPE) bottles of 100 and 500.

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; therefore, discontinuation of diuretic therapy may be required.

Use of ALTACE should include appropriate assessment of renal function.

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

Angioedema has been reported in patients with ACE inhibitors including ALTACE. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, ALTACE 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 subcutaneous epinephrine solution 1:1000) should be administered promptly (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Essential Hypertension; Less Common Clinical Trial Adverse Drug Reactions (<1%), Body as a Whole).

Since the use of ALTACE 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 and the use of ALTACE should be stopped.

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 ALTACE and consult with their physician.

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases facial angioedema also occurred. The intestinal angioedema symptoms resolved after stopping the ACE inhibitor.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

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

Angioedema, including laryngeal edema, may occur especially following the first dose of ALTACE.

ALTACE may lower the state of patient alertness and/or reactivity, particularly at the start of treatment (see Adverse Reactions).

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, ALTACE 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, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

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

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.

Use of ALTACE should include appropriate assessment of renal function, particularly in the initial week's treatment with an ACE inhibitor. Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency.

Particularly careful monitoring is required in patients with: heart failure; renovascular disease, including patients with haemodynamically relevant unilateral renal artery stenosis. In the latter patient group, even a small increase in serum creatinine may be indicative of unilateral loss of renal function; impairment of renal function; kidney transplant.

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 ALTACE (see Adverse Reactions). Should the patient receiving ALTACE 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 ALTACE should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. In patients with impaired liver function, response to the treatment with ALTACE may be either increased or reduced. ALTACE should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply (see Action and Clinical Pharmacology, Special Populations and Conditions, Hepatic Insufficiency).

Rarely, ACE inhibitors, including ALTACE, 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.

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

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.

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

In patients undergoing surgery or anesthesia with agents producing hypotension, ALTACE 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.

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Patients should be told to report promptly to their physician any indication of infection (e.g. sore throat, fever) as this may be a sign of neutropenia (see Adverse Reactions).

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

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

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

Periodic monitoring of white blood cell counts should be considered to permit detection of a possible leukopenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma) or those treated with other drugs that can cause changes in the blood picture (see Drug Interactions, Drug-Drug Interactions, Allopurinol, Immunosuppressants, Corticosteroids, Procainamide, Cytostatics and Other Substances That May Change the Blood Picture).

No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. The doses used were: 10, 100, or 1000 mg/kg in rats (2500 times maximum human dose), 0.4, 1.0, or 2.5 mg/kg in rabbits (6.25 times maximum human dose), and 5, 50, or 500 mg/kg in cynomolgus monkeys (1250 times maximum human dose). In rats, the highest dose caused reduced food intake in the dams, with consequent reduced birth weights of the pups and weight development during the lactation period. In rabbits, maternal effects were mortalities (high and middle dose) and reduced body weight. In monkeys, maternal effects were mortalities (high and middle dose), vomiting, and reduced weight gain.

Patients should be cautioned to report lightheadedness, especially during the first few days of ALTACE 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.

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of ALTACE, has been reported. Such possibility should be considered as part of the differential diagnosis of cough (see Adverse Reactions).

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

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.

The presence of concentrations of ACE inhibitor have been reported in human milk. The use of ALTACE is contraindicated during breast-feeding.

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.

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 Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

Following absorption, ramipril is rapidly hydrolyzed in the liver to its active 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 is 56%.

Following oral administration, ramipril is rapidly absorbed with peak plasma concentrations occurring within 1 hour. The extent of absorption of ramipril is 50-60% and is not significantly altered by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.

Following a single administration of up to 5 mg of ramipril, plasma concentrations of ramipril and ramiprilat increase in a manner that is greater than proportional to dose; after a single administration of 5 mg to 20 mg of ramipril the plasma concentrations for both are dose-proportional. The non-linear pharmacokinetics observed at the lower doses of ramipril can be explained by the saturable binding of ramiprilat to ACE. At steady-state, the 24-hour AUC for ramiprilat is dose-proportional over the recommended dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44% respectively when 5 mg of oral ramipril was compared to 5 mg given intravenously.

Plasma concentrations of ramiprilat decline in a triphasic manner. The initial rapid decline, which represents distribution of the drug, has a half life of 2-4 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 9-18 hours, and the terminal elimination phase has a prolonged half-life of >50 hours. After multiple daily doses of ramipril 5-10 mg, the half-life of ramiprilat concentrations was 13-17 hours, but was considerably prolonged at 2.5 mg (27-36 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 ALTACE especially at low doses (2.5 mg).

ALTACE is an angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of essential hypertension, following acute myocardial infarction in stabilized patients with clinically confirmed heart failure, and for the management of patients at increased risk of cardiovascular events.

Following oral administration, ALTACE 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 Warnings and Precautions, Hematologic, Hyperkalemia and Potassium-sparing Diuretics). Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion result in increases in plasma renin activity.

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

The antihypertensive effect of angiotension converting enzyme inhibitors is generally lower in black patients than in non-blacks.

After oral administration of ALTACE, about 60% of the parent drug and its metabolites is excreted in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. In patients with creatinine clearance <40 mL/min/1.73 m², increases in C_max and AUC of ramipril and ramiprilat compared to normal subjects were observed following multiple dosing with 5 mg ramipril (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Use in Renal Impairment).

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.

Administration of ALTACE 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 and Precautions).

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

The effectiveness of ALTACE 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 ALTACE 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 ALTACE lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system, ALTACE has an antihypertensive effect even in patients with low-renin hypertension.

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

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