Hypertension

Altace has been evaluated for safety in over 4,000 patients with hypertension; of these, 1,230 patients were studied in US controlled trials, and 1,107 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 Altace and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving Altace in US placebo-controlled trials were: headache (5.4%), “dizziness” (2.2%) and fatigue or asthenia (2.0%), but only the last was more common in Altace 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 US patients treated with Altace. The most common reasons for discontinuation were: cough (1.0%), “dizziness” (0.5%), and impotence (0.4%).

Of observed side effects considered possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% vs 1%).

PATIENTS IN US PLACEBO CONTROLLED STUDIES

In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the ramipril group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of these patients requiring discontinuation of treatment.

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 and more frequently on ramipril are shown below. The incidences represent the experiences from the AIRE study. The follow-up time was between 6 and 46 months for this study.

Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug

Placebo-Controlled (AIRE) Mortality Study

HOPE Study:

Safety data in the HOPE trial were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the AIRE trial. The rate of angioedema was the same as in previous clinical trials (see WARNINGS).

Other adverse experiences reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in postmarketing experience, include the following (in some, a causal relationship to drug use is uncertain):

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

Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in US trials) (See WARNINGS and PRECAUTIONS), syncope and palpitations.

Hematologic: Pancytopenia, hemolytic anemia and thrombocytopenia.

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

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

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

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

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. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.

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.

Post-Marketing Experience: In addition to adverse events reported from clinical trials, there have been rare reports of hypoglycemia reported during Altace therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.

Clinical Laboratory Test Findings:

Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving Altace alone, and in 1.5% of patients receiving Altace and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving Altace alone and in 3% of patients Altace 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 Altace alone and in 1.5% of patients receiving Altace plus a diuretic. No US 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 Altace 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 US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

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.

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 Altace. The possibility of hypotensive effects with Altace can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, the starting dose should be reduced. (See DOSAGE AND ADMINISTRATION.)

With potassium supplements and potassium-sparing diuretics: Altace 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.

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

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