ACEONÒ (perindopril erbumine) Tablets has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. ACEONÒ Tablets was in general well-tolerated in the patient populations studied, the side effects were usually mild and transient. Although dizziness was reported more frequently in placebo patients (8.5%) than in perindopril patients (8.2%), the incidence appeared to increase with an increase in perindopril dose.

The data presented here are based on results from the 1,417 ACEONÒ Tablets-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with ACEONÒ Tablets for at least one year.

In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with ACEONÒ Tablets and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia and dizziness.

Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with ACEONÒ Tablets and in those treated with placebo (approximately 75% in each group). Adverse events that occurred in 1% or greater of the patients and that were more common for perindopril than placebo by at least 1% (regardless of whether they were felt to be related to study drug) are shown in the first two columns below. Of these adverse events, those considered possibly or probably related to study drug are shown in the last two columns.

Of these, cough was the reason for withdrawal in 1.3% of perindopril and 0.4% of placebo patients. While dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), it was clearly increased with dose, suggesting a causal relationship with perindopril. Other commonly reported complaints (1% or greater), regardless of causality, include: headache (23.8%), upper respiratory infection (8.6%), asthenia (7.9%), rhinitis (4.8%), low extremity pain (4.7%), diarrhea (4.3%), edema (3.9%), pharyngitis (3.3%), urinary tract infection (2.8%), abdominal pain (2.7%), sleep disorder (2.5%), chest pain (2.4%), injury, paresthesia, nausea, rash (each 2.3%), seasonal allergy, depression (each 2.0%), abnormal ECG (1.8%), ALT increase (1.7%), tinnitus, vomiting (each 1.5%), neck pain, male sexual dysfunction (each 1.4%), triglyceride increase, somnolence (each 1.3%), joint pain, nervousness, myalgia, menstrual disorder (each 1.1%), flatulence and arthritis (each 1.0%), but none of those was more frequent by at least 1% on perindopril than on placebo. Depending on the specific adverse event, approximately 30 to 70% of the common complaints were considered possibly or probably related to treatment.

Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension.

Below is a list (by body system) of adverse experiences reported in 0.3 to 1% of patients in U.S. placebo-controlled studies in hypertensive patients without regard to attribution to therapy. Less frequent but medically important adverse events are also included; the incidence of these events is given in parentheses.

Body as a Whole: malaise, pain, cold/hot sensation, chills, fluid retention, orthostatic symptoms, anaphylactic reaction, facial edema, angioedema (0.1%).

Gastrointestinal: constipation, dry mouth, dry mucous membrane, appetite increased, gastroenteritis.

Respiratory: posterior nasal drip, bronchitis, rhinorrhea, throat disorder, dyspnea, sneezing, epistaxis, hoarseness, pulmonary fibrosis (<0.1%).

Urogenital: vaginitis, kidney stone, flank pain, urinary frequency, urinary retention.

Cardiovascular: hypotension, ventricular extrasystole, myocardial infarction, vasodilation, syncope, abnormal conduction, heart murmur, orthostatic hypotension.

Endocrine: gout.

Hematology: hematoma, ecchymosis.

Musculoskeletal: arthralgia, myalgia.

CNS: migraine, amnesia, vertigo, cerebral vascular accident (0.2%).

Psychiatric: anxiety, psychosexual disorder.

Dermatology: sweating, skin infection, tinea, pruritus, dry skin, erythema, fever blisters, purpura (0.1%).

Special Senses: conjunctivitis, earache.

Laboratory: potassium decrease, uric acid increase, alkaline phosphatase increase, cholesterol increase, AST increase, creatinine increase, hematuria, glucose increase.

When ACEONÒ Tablets was given concomitantly with thiazide diuretics, adverse events were generally reported at the same rate as those for ACEONÒ Tablets alone, except for a higher incidence of abnormal laboratory findings known to be related to treatment with thiazide diuretics alone (e.g., increases in serum uric acid, triglycerides and cholesterol and decreases in serum potassium).

Potential Adverse Effects Reported with ACE Inhibitors: Other medically important adverse effects reported with other available ACE inhibitors include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigus, acute pancreatitis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia or an elevated ESR. Many of these adverse effects have also been reported for perindopril.

Fetal/Neonatal Morbidity and Mortality: See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Hematology, clinical chemistry and urinalysis parameters have been evaluated in U.S. placebo-controlled trials. In general, there were no clinically significant trends in laboratory test findings.

Hyperkalemia: In clinical trials, 1.4% of the patients receiving ACEONÒ Tablets and 2.3% of the patients receiving placebo showed serum potassium levels greater than 5.7 mEq/L. (See PRECAUTIONS.)

BUN/Serum Creatinine Elevations: Elevations, usually transient and minor, of BUN and serum creatinine have been observed. In placebo-controlled clinical trials, the proportion of patients experiencing increases in serum creatinine were similar in the ACEONÒ Tablets and placebo treatment groups. Rapid reduction of long-standing or markedly elevated blood pressure by any antihypertensive therapy can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. (See PRECAUTIONS.)

Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with ACEONÒ Tablets, but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials (See WARNINGS.)

Liver Function Tests: Elevations in ALT (1.6% ACEONÒ Tablets vs 0.9% placebo) and AST (0.5% ACEONÒ Tablets vs 0.4% placebo) have been observed in U.S. placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.

Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEONÒ Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEONÒ Tablets, for at least two hours and until blood pressure has stabilized for another hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.)

The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.

Potassium Supplements and Potassium-Sparing Diuretics: ACEONÒ Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) 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.

Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEONÒ Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.

Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution.

Food Interaction: Oral administration of ACEONÒ Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state.

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