ACEON®
(perindopril erbumine) Tablets

Rx Only

500063/500064   Rev May 2005

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ACEON® Tablets should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

ACEON® (perindopril erbumine) Tablets is the tert-butylamine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Perindopril erbumine is chemically described as (2S,3∝S,7∝S)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1). Its molecular formula is C₁₉H₃₂N₂O₅C₄H₁₁N. Its structural formula is:

Perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform.

Perindopril is the free acid form of perindopril erbumine, is a pro-drug and metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.

ACEON® Tablets is available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to perindopril erbumine, each tablet contains the following inactive ingredients: colloidal silica (hydrophobic), lactose, magnesium stearate and microcrystalline cellulose. The 4 and 8 mg tablets also contain iron oxide.

The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108). The mean follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.

The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of perindopril on the primary outcome was evident after about one year of treatment (Figure 1).

The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).

ACEON® (perindopril erbumine) Tablets is indicated in patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction. ACEON® Tablets can be used with conventional treatment for management of coronary artery disease, such as antiplatelet, antihypertensive or lipid-lowering therapy.

ACEON® (perindopril erbumine) Tablets is indicated for the treatment of patients with essential hypertension. ACEON® Tablets may be used alone or given with other classes of antihypertensives, especially thiazide diuretics.

When using ACEON® Tablets, consideration should be given to the fact that another angiotensin converting enzyme inhibitor (captopril) has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Available data are insufficient to determine whether ACEON® Tablets has a similar potential. (See WARNINGS.)

In considering use of ACEON® Tablets, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in nonblacks. In addition, it should be noted that black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to nonblacks. (See WARNINGS: Head and Neck Angioedema.)

ACEON® (perindopril erbumine) Tablets is contraindicated in patients known to be hypersensitive to this product or to any other ACE inhibitor. ACEON® Tablets is also contraindicated in patients with a history of angioedema related to previous treatment with an ACE inhibitor.

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.

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 ul (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 bulers, 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).

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.

In animals, doses of perindopril up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal. Past experiences were scant but suggested that overdosage with other ACE inhibitors was also fairly well tolerated by humans. The most likely manifestation is hypotension, and treatment should be symptomatic and supportive. Therapy with the ACE inhibitor should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.

However, of the reported cases of perindopril overdosage, one (dosage unknown) required assisted ventilation and the other developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of perindopril. The intervention for perindopril overdose may require vigorous support (see below).

Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of perindopril overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of perindopril and its metabolites. Perindopril can be removed by hemodialysis, with clearance of 52 mL/min for perindopril and 67 mL/min for perindoprilat.

Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of perindopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of perindopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat perindopril overdose by infusion of normal saline solution.

In patients with stable coronary artery disease, ACEON® Tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (>70 yrs), ACEON® Tablets should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.

Kinetic data indicate that perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when creatinine clearance drops below 30 mL/min. In such patients (creatinine clearance <30 mL/min), safety and efficacy of ACEON® Tablets have not been established. For patients with lesser degrees of impairment (creatinine clearance above 30 mL/min), the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day due to limited clinical experience. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.

Tablets 2 mg: Scored one side, white, oblong (debossed “ACN 2” on one side and debossed with “SLV” on both sides of score on the other side)

Bottles of 100                                       NDC 0032-1101-01

Tablets 4 mg: Scored one side, pink, oblong (debossed “ACN 4” on one side and debossed with “SLV” on both sides of score on the other side)

Bottles of 100                                       NDC 0032-1102-01

Tablets 8 mg: Scored one side, salmon-colored, oblong (debossed “ACN 8” on one side and debossed with “SLV” on both sides of score on the other side)

Bottles of 100                                       NDC 0032-1103-01

Storage Conditions: Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Protect from moisture.

Keep out of the reach of children.

Manufactured by:
Patheon Pharmaceuticals, Inc.
Cincinnati, OH 45237 USA

Marketed by:
Solvay Pharmaceuticals, Inc.
Marietta, GA 30062

© 2005 Solvay Pharmaceuticals, Inc.

500063/500064   Rev May 2005