SIDE EFFECTS

Hypertension: Ramipril has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in ramipril and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in U.S. placebo-controlled trials were: headache (5.4%), "dizziness" (2.2%) and fatigue or asthenia (2.0%), but only the last was more common in ramipril patients than in patients given placebo. Generally, the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 to 20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with ramipril. The most common reasons for discontinuation were: cough (1.0%), "dizziness" (0.5%), and impotence (0.4%).

The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with ramipril are shown in TABLE 1.

Heart Failure Post Myocardial Infarction: Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than one percent of patients with heart failure treated with ramipril are shown in TABLE 2. The incidences represent the experiences from the AIRE study. The follow-up time was between 6 and 46 months for this study.

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

Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) (See WARNINGS and PRECAUTIONS), syncope (not reported in U.S. trials), angina pectoris, arrhythmia, chest pain, palpitations, myocardial infarction, and cerebrovascular events.

Hematologic: Pancytopenia, hemolytic anemia and thrombocytopenia.

Renal: Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking ramipril, particularly when ramipril was given concomitantly with a diuretic. (See WARNINGS.)

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

Cough: A tickling, dry, persistent, nonproductive cough has been reported with the use of ACE inhibitors. Approximately 1% of patients treated with ramipril have required discontinuation because of cough. The cough disappears shortly after discontinuation of treatment. (See PRECAUTIONS, Cough.)

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

Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), erythema multiforme, pemphigus, photosensitivity, pemphigoid, Stevens-Johnson syndrome, toxic epidermal necrolysis, and onycholysis and purpura.

Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.

Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.

Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/neonatal morbidity and mortality.

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

Clinical Laboratory Test Findings

Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis. (See WARNINGS and PRECAUTIONS.) Since ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Potassium supplements and potassium-sparing diuretics should be given with caution, and the patient's serum potassium should be monitored frequently. (See WARNINGS and PRECAUTIONS.)

Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dl or 5% respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin or hematocrit.

Other (Causal Relationships Unknown): Clinically important changes in standard laboratory tests were rarely associated with ramipril administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leukopenia, eosinophilia, and proteinuria. In U.S. trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities: all of these were cases of proteinuria or abnormal liver-function tests.

DRUG INTERACTIONS

With Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, the starting dose should be reduced. (See DOSAGE AND ADMINISTRATION.)

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

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

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

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