• ACEON is indicated for the treatment of patients with essential hypertension (1.1)
• ACEON is indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction (1.2)

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

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

Hypertension

• The recommended initial dose is 4 mg once a day. The dosage may be titrated upward until blood pressure, when measured just before the next dose, is controlled or to a maximum of 16 mg per day (2.1)

Stable Coronary Artery Disease

• ACEON 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 (2.2)

Use in Uncomplicated Hypertensive Patients:  In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.

Use in Elderly Patients:  The recommended initial daily dosage of ACEON for the elderly is 4 mg daily, given in one or two divided doses. Experience with ACEON is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration [see Use in Specific Populations (8.5)].

Use with Diuretics:  In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of ACEON. Consider reducing the dose of diuretic prior to starting ACEON [see Drug Interactions (7.1)].

In patients with stable coronary artery disease, ACEON 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 (greater than 70 years), ACEON 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.

Perindoprilat elimination is decreased in renally impaired patients. ACEON is not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.

ACEON^® (perindopril erbumine) is contraindicated in patients known to be hypersensitive (including angioedema) to this product or to any other ACE inhibitor. ACEON is also contraindicated in patients with hereditary or idiopathic angioedema.

Do not co-administer aliskiren with ACEON in patients with diabetes [see Drug Interactions (7.8)].

• Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema (4.0, 5.1)
• Do not co-administer aliskiren with ACEON in patients with diabetes (4.0, 7.8)

• Watch for anaphylactoid reactions, including angioedema (5.1)
• Monitor renal function during therapy (5.8)
• Assess for hypotension and hyperkalemia (5.2, 5.6)

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ACEON) may be subject to a variety of adverse events, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

Head and Neck Angioedema:  Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors, including ACEON (0.1% of patients treated with ACEON in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue ACEON treatment immediately and observe until the swelling disappears. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.

Intestinal Angioedema:  Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

ACEON can cause symptomatic hypotension. ACEON has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.

Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting [see Dosage and Administration (2.1)].

ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

In patients at risk of excessive hypotension, ACEON therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of ACEON and/or diuretic is increased.

If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. ACEON treatment can usually be continued following restoration of volume and blood pressure.

ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected discontinue ACEON as soon as possible [see Use in Specific Populations (8.1)].

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving ACEON [see Dosage and Administration (2.3)], [see Drug Interactions (7.8)].

In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ACEON, may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure and death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor. In such patients, renal function should be monitored during the first few weeks of therapy.

Some ACEON-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in those concomitantly treated with a diuretic.

Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including ACEON. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.2)].

Serum potassium should be monitored periodically in patients receiving ACEON.

Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

In patients undergoing surgery or during anesthesia with agents that produce hypotension, ACEON may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• Hypertension: Most common adverse events (incidence greater than or equal to 5%) are cough, dizziness and back pain (6.1)
• Stable Coronary Artery Disease: Most common adverse events leading to discontinuation were cough, drug intolerance, and hypotension (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact XOMA (US) LLC at 1-800-718-9884 or FDA at 1-800-FDA-1088 or www.FDA.gov/Medwatch.

The following adverse reactions are discussed elsewhere in labeling:

• Anaphylactoid reactions, including angioedema [see Warnings and Precautions (5.1)]
• Hypotension [see Warnings and Precautions (5.2)]
• Neutropenia and agranulocytosis [see Warnings and Precautions (5.3)]
• Impaired renal function [see Warnings and Precautions (5.5)]
• Hyperkalemia [see Warnings and Precautions (5.6)]
• Cough [see Warnings and Precautions (5.7)]

Hypertension

ACEON has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented here are based on results from the 1,417 ACEON-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with ACEON^® (perindopril erbumine) 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 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 and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on ACEON was at least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).

Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with perindopril.

Stable Coronary Artery Disease

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.

Voluntary reports of adverse events in patients taking ACEON that have been received since market introduction and are of unknown causal relationship to ACEON 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 pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive antinuclear antibody (ANA), leukocytosis, eosinophilia or an elevated erythrocyte sedimentation rate (ESR).

Hematology:  Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with ACEON, 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 and Precautions (5.3)].

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