SIDE EFFECTS

ACEON® (perindopril erbumine) Tablets has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. ACEON® 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 ACEON® Tablets -treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with ACEON® 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 ACEON® 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 ACEON® 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.

FREQUENCY OF ADVERSE EVENTS (%)
	All Adverse Events		Possibly – or Probably – Related Adverse Events
	Perindopril n=789	Placebo n=223	Perindopril n=789	Placebo n=223
Cough	12.0	4.5	6.0	1.8
Back Pain	5.8	3.1	0.0	0.0
Sinusitis	5.2	3.6	0.6	0.0
Viral Infection	3.4	1.6	0.3	0.0
Upper Extremity Pain	2.8	1.4	0.2	0.0
Hypertonia	2.7	1.4	0.2	0.0
Dyspepsia	1.9	0.9	0.3	0.0
Fever	1.5	0.5	0.3	0.0
Proteinuria	1.5	0.5	1.0	0.5
Ear Infection	1.3	0.0	0.0	0.0
Palpitation	1.1	0.0	0.9	0.0

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.

Below is a list (by body system) of adverse experiences reported in 0.3 to 1% of patients in U.S. placebo-controlled studies 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 ACEON® Tablets was given concomitantly with thiazide diuretics, adverse events were generally reported at the same rate as those for ACEON® 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.

Clinical Laboratory Test Findings: 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 ACEON® 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 ACEON® 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 ACEON® 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% ACEON® Tablets vs 0.9% placebo) and AST (0.5% ACEON® 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.

DRUG INTERACTIONS

Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON® 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 ACEON® 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: ACEON® 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 ACEON® 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 ACEON® 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks.

Mutagenesis: No genotoxic potential was detected for ACEON® Tablets, perindoprilat and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, TK ± mouse lymphoma assay, mouse and rat micronucleus tests and Chinese hamster bone marrow assay.

Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of ACEON® Tablets during the period of spermatogenesis in males or oogenesis and gestation in females.

Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimesters). (See WARNINGS: Fetal/Neonatal Morbidity and Mortality.)

Nursing Mothers: Milk of lactating rats contained radioactivity following administration 14C-perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when ACEON® Tablets is given to nursing mothers.

Pediatric Use: Safety and effectiveness of ACEON® Tablets in pediatric patients have not been established.

Geriatric Use: The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 than in younger patients, although the difference was not significant. Plasma concentrations of both perindopril and perindoprilat were increased in elderly patients compared to concentrations in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and possibly rash. Experience with ACEON® Tablets in elderly patients at daily doses exceeding 8 mg is limited.