ALTACE (ramipril) is indicated for:

• Essential Hypertension: ALTACE is indicated in the treatment of essential hypertension. It may be used alone or in association with thiazide diuretics.

  
  

  ALTACE 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.

  
  

  ALTACE 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 ALTACE 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 ALTACE with antihypertensive agents other than thiazide diuretics or calcium channel blocker felodipine have not been established.

  
  

• Treatment Following Acute Myocardial Infarction: ALTACE 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 and Precautions, Cardiovascular, Hypotension).

  
  

• Management of Patients at Increased Risk of Cardiovascular Events: ALTACE may be used to reduce the risk of myocardial infarction, stroke or cardiovascular death in patients over 55 years of age who are at high risk of cardiovascular events because of a history of coronary artery disease, stroke, peripheral artery disease, or diabetes that is accompanied by at least one other cardiovascular risk factor such as hypertension, elevated total cholesterol levels, low high density lipoprotein levels, cigarette smoking, or documented microalbuminuria.

  
  

 

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.

ALTACE is contraindicated in:

• Patients who are hypersensitive to this drug, to any other ACE inhibitor, or to any ingredient in the formulation. For a complete listing of ingredients see Dosage Forms, Composition and Packaging.

  
  

• Patients who have a history of angioedema.

  
  

• During pregnancy

  
  

• In breast-feeding women

  
  

 

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).

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

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.

Symptomatic hypotension has occurred after administration of ALTACE, 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 Reactions, Clinical Trial Adverse Drug Reactions, Treatment Following Acute Myocardial Infarction, Management of Patients at Increased Risk of Cardiovascular Events and Less Common Clinical Trial Adverse Drug Reactions (<1%), Cardiovascular). Because of the potential fall in blood pressure in these patients, therapy with ALTACE should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of ALTACE 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 intravenous 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 ALTACE and/or reduced concomitant diuretic therapy should be considered. In patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of ALTACE (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Treatment Following Acute Myocardial Infarction, Dosage and Administration, Recommended Dose and Dosage Adjustment, Treatment Following Acute Myocardial Infarction).

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).

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 ALTACE 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. (See Warnings and Precautions, Monitoring and Laboratory Tests.)

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. 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.

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.

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).

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.

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.

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.

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.

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 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.

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.

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.

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

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

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).

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.

Use of ALTACE should include appropriate assessment of renal function. Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency.

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.

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

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).

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.

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.

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.

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%).

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.

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.

1004 post-AMI patients received ALTACE 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 ALTACE following an acute myocardial infarction are shown below. 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). See Table 1 and Table 2.

Table 1: ALTACE

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

Adverse Event	Ramipril n=1004 %	Placebo n=982 %
Hypotension	10.7	4.7
Cough Increased	7.6	3.7
Dizziness/Vertigo	5.6	3.9
Nausea/Vomiting	3.8	1.9
Angina Pectoris	2.9	2.0
Postural Hypotension	2.2	1.4
Syncope	2.1	1.4
Heart Failure	2.0	2.2
Severe/resistant Heart Failure	2.0	3.0
Myocardial Infarct	1.7	1.7
Vomiting	1.6	0.5
Headache	1.2	0.8
Abnormal Kidney Function	1.2	0.5
Abnormal Chest Pain	1.1	0.9
Diarrhea	1.1	0.4

Table 2: ALTACE

Percentage of Patients with Serious Adverse Events Possibly Related to Study Drug Placebo-controlled (AIRE) Mortality Study

Adverse Event	ALTACE n=1004 %	Placebo n=982 %
Hypotension	3.0	1.1
Angina Pectoris	2.0	1.2
Severe/resistant Heart Failure	1.9	2.9
Myocardial Infarct	1.7	1.7
Heart Failure	1.5	1.5
Syncope	1.3	0.8
Chest Pain	0.7	0.9
Nausea	0.6	0.5
Vomiting	0.5	0.1
Dizziness	0.5	0.5
Abnormal Kidney Function	0.5	0.2
Chest Infection	0.2	0.0
Postural Hypotension	0.2	0.2
Headache	0.1	0.0

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%).

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%).

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:

anaphylactoid reactions, angioedema.

symptomatic hypotension, syncope, angina pectoris, arrhythmia, chest pain, palpitations, tachycardia, myocardial infarction, cerebrovascular disorders (including ischaemic stroke).

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

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, maculo-papular exanthema, psoriasiform exanthema, pemphigoid exanthema and enanthema, and toxic epidermal necrolysis or onycholysis.

hepatic failure, cholestatic jaundice, hepatitis, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, nausea, increased salivation, smell and taste disturbance vomiting.

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.

agranulocytosis, leucopenia, eosinophilia, thrombocytopenia, pancytopaenia and hemolytic anemia.

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

increased cough.

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 leucocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur.

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

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).

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.)

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

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.

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.

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

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 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.)

ACE inhibitors may reduce insulin resistance. In isolated cases, such reduction may lead to hypoglycaemic reactions in patients concomitantly treated with antidiabetics. Particularly close blood glucose monitoring is, therefore, recommended in the initial phase of co-administration.