Aceon

Aceon information, interactions and side effects, ACEON® (perindopril erbumine) Tablets contain 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:

aceon

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 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 mg and 8 mg tablets also contain iron oxide.

INDICATIONS

Hypertension

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.

Stable Coronary Artery Disease

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.

DOSAGE AND ADMINISTRATION

Hypertension

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.

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.

Stable Coronary Artery Disease

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.

Dose Adjustment in Renal Impairment and Dialysis

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.

HOW SUPPLIED

Dosage Forms And Strengths

Tablets are oblong with a score on one side.

2 mg tablet is white and debossed on the unscored side with “ACN 2”.

4 mg tablet is pink and debossed on the unscored side with “ACN 4”.

8 mg tablet is salmon and debossed on the unscored side with “ACN 8”.

Storage And Handling

Tablets are oblong with a score on one side.

 

Tablets Appearance NDC (Bottles of 100)
2 mg White, debossed “ACN 2” on unscored side NDC 76234-000-01
4 mg Pink, debossed “ACN 4” on unscored side NDC 76234-001-01
8 mg Salmon-colored, debossed “ACN 8” on unscored side NDC 76234-002-01

Keep out of the reach of children.

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

For further information, please call our medical communications department toll-free 1-800-718-9884.

Manufactured by: Patheon Pharmaceuticals, Inc., Cincinnati, OH 45237 USA. Marketed by: XOMA (US) LLC Berkeley, CA 94710 USA. Rev Jan 2012

This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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.

Clinical Trials Experience

The following adverse reactions are discussed elsewhere in labeling:

  • Anaphylactoid reactions, including angioedema
  • Hypotension
  • Neutropenia and agranulocytosis
  • Impaired renal function
  • Hyperkalemia
  • Cough
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.

Postmarketing Experience

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).

Clinical Laboratory Test Findings

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.

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.

DRUG INTERACTIONS

Diuretics

Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of ACEON, for at least two hours and until blood pressure has stabilized for another hour.

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 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, monitor the patient’s serum potassium frequently.

Lithium

Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and WARNING: AVOID USE IN PREGNANCYWhen pregnancy is detected, discontinue ACEON as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury to or death of the developing fetus (5.4)

ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including ACEON.

Digoxin

A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON, 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.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including perindopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving perindopril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.

PRECAUTIONS

Anaphylactoid and Possibly Related Reactions

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.

Hypotension

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.

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.

Neutropenia/Agranulocytosis

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.

Fetal/Neonatal Morbidity and Mortality

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development.

Prematurity, intrauterine growth retardation, patent ductus arteriosus, and other structural cardiac malformations, as well as neurologic malformations, have been reported following exposure to ACE inhibitors during the first trimester of pregnancy.

When patients become pregnant, healthcare providers should make every effort to discontinue the use of ACEON as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, ACEON® (perindopril erbumine) should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and healthcare providers should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.

Impaired Renal Function

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.

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.

Hyperkalemia

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.

Serum potassium should be monitored periodically in patients receiving ACEON.

Cough

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.

Hepatic Failure

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.

Surgery/Anesthesia

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

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, 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 during the period of spermatogenesis in males or oogenesis and gestation in females.

Use In Specific Populations

Pregnancy

Pregnancy Category D. Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.

Nursing Mothers

Milk of lactating rats contained radioactivity following administration of 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 is given to nursing mothers.

Pediatric Use

Safety and effectiveness of ACEON 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.

Start at a low dose and titrate slowly as needed. Monitor for dizziness because of potential for falls.

Experience with ACEON in elderly patients at daily doses exceeding 8 mg is limited.

Renal Impairment

Dosage adjustment may be necessary in renally impaired patients.

Hepatic Impairment

The bioavailability of perindoprilat is increased in patients with impaired hepatic function.

This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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.

Among the reported cases of perindopril overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of perindopril. The intervention for perindopril overdose may require vigorous support.

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.

CONTRAINDICATIONS

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.

This monograph has been modified to include the generic and brand name in many instances.

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