Source: Health Products and Food Branch (CA) Revision Year: 2006
RAMACE (ramipril) is contraindicated:
Angioedema has been reported in patients with ACE inhibitors including RAMACE (ramipril). Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, RAMACE 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 0.5ml of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS).
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).
Symptomatic hypotension has occurred after administration of RAMACE, 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). Because of the potential fall in blood pressure in these patients, therapy with RAMACE should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of RAMACE 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 RAMACE and/or reduced concomitant diuretic therapy should be considered. In patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of RAMACE (see ADVERSE REACTIONS – Treatment Following Acute Myocardial Infarction, DOSING & ADMINISTRATION – Treatment Following Acute Myocardial Infarction).
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 RAMACE 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.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, RAMACE 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.
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 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 RAMACE is contraindicated during breast-feeding.
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 RAMACE should include appropriate assessment of renal function.
RAMACE 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.
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 (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.
Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials treated with RAMACE. 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).
In patients undergoing surgery or anesthesia with agents producing hypotension, RAMACE 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.
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.
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 RAMACE (see ADVERSE REACTIONS). Should the patient receiving RAMACE 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 RAMACE should be considered when appropriate.
There are no adequate studies in patients with cirrhosis and/or liver dysfunction. RAMACE 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.
The safety and effectiveness of RAMACE 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, Pharmacokinetics).
RAMACE may lower the state of patient alertness and/or reactivity, particularly at the start of treatment (see ADVERSE REACTIONS).
A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of RAMACE, has been reported. Such possibility should be considered as part of the differential diagnosis of cough (see ADVERSE REACTIONS).
RAMACE (ramipril) 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=1,244), angioedema occurred in 0.1% patients treated with ramipril and a diuretic.
The most frequent adverse events occurring in these trials with RAMACE 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 RAMACE patients, with about 4% of these patients requiring discontinuation of treatment. Approximately 1% of patients treated with RAMACE monotherapy in North American controlled clinical trials (n=972) have required discontinuation because of cough.
1004 post-AMI patients received RAMACE 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 RAMACE 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).
| 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 |
| 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 – 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 RAMACE 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 RAMACE in controlled clinical trials, or seen in post-marketing 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, tachycardia, myocardial infarction, cerebrovascular disorders (including ischaemic stroke).
Respiratory: increased cough.
CNS: anxiety, amnesia, confusion, 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 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.
Gastrointestinal: abdominal pain (sometimes with enzyme changes suggesting pancreatitis), pancreatitis, anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, hepatitis, nausea, increased salivation, smell and taste disturbance, vomiting.
Renal: increases in blood urea nitrogen (BUN) and serum creatinine.
Haematologic: agranulocytosis, leucopenia, eosinophilia, thrombocytopenia, pancytopaenia 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 leucocytosis. 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; 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 RAMACE can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with RAMACE. If it is not possible to discontinue the diuretic, the starting dose of RAMACE 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 AND ADMINISTRATION).
Since RAMACE 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 PRECAUTIONS – Drug Interactions – Non-steroidal anti-inflammatory agents)
The antihypertensive effect of RAMACE 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 RAMACE 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 RAMACE 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 PRECAUTIONS – Drug Interactions – 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.
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