Aceon

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away.

You should not use perindopril if you have hereditary angioedema.

If you have diabetes, do not use perindopril together with any medication that contains aliskiren (such as Amturnide, Tekturna, Tekamlo).

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

• If you have an allergy to perindopril erbumine or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have ever had a very bad or life-threatening reaction called angioedema. Signs may be swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; unusual hoarseness.
• If you have kidney disease.
• If you are taking a drug that has aliskiren in it and you also have high blood sugar (diabetes) or kidney problems. Check with your doctor or pharmacist if you are not sure if a drug you take has aliskiren in it.
• If you have taken a drug that has sacubitril in it in the last 36 hours.

This is not a list of all drugs or health problems that interact with Aceon.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use Aceon as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine at the same time of day.
• To gain the most benefit, do not miss doses.
• Keep taking Aceon as you have been told by your doctor or other health care provider, even if you feel well.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Cough.
• Dizziness.
• Back pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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 [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)].

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.

Mechanism of Action

Aceon® (perindopril erbumine) is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.

ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Aceon remains to be elucidated.

While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.

Pharmacodynamics

After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.

Pharmacokinetics

Absorption:  Oral administration of Aceon results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after perindopril administration. Oral administration of Aceon 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.

With 4 mg, 8 mg and 16 mg doses of Aceon, Cmax and AUC of perindopril and perindoprilat increase in a dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.

Distribution:  Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.

Metabolism and Elimination:  Following oral administration perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1 hours.

Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril.

The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of Aceon. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once daily dosing with perindopril, perindoprilat accumulates about 1.5 to 2 fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.

Elderly:  Plasma concentrations of both perindopril and perindoprilat in elderly patients (greater than 70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat [see Dosage and Administration (2.1) and Use In Specific Populations (8.5)].

Heart Failure:  Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.

Renal Impairment:  With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.

In a limited number of patients studied, perindopril clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min [see Dosage and Administration (2.3)].

Hepatic Impairment:  The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.

Aceon is a prescription medication used to treat high blood pressure.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Take Aceon exactly as prescribed. Follow the directions on your prescription label carefully.

The recommended starting dose of Aceon is usually 4 mg once daily. Your healthcare provider may increase your dose if necessary to achieve the desired blood pressure response. The usual recommended dosing range is between 4 mg and 8 mg a day.

Based on how your body responds to the medication and side effects you experience your healthcare provider may decide to increase or decrease your dose. The dose you receive is also based on the following factors:

• your age
• the medical condition you are being treated for
• other medical conditions you may have 
• other medications you are taking including diuretics

• Store at room temperature between 20° and 25°C (68° and 77°F).
• Keep this and all medications out of the reach of children.

Pregnancy Category: D

Discontinue as soon as pregnancy detected; during the second and third trimesters of pregnancy, drugs that act directly on the renin-angiotensin have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death

Lactation: not known if distributed into breast milk; use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Angiotensin converting enzyme (ACE) inhibitors dilate arteries and veins by competively inhibiting the conversion of angiotensin I to angiotensin II (a potent endogenous vasoconstrictor) and by inhibiting bradykinin metabolism; these actions result in preload and afterload reductions on the heart

ACE inhibitors also promote sodium and water excretion by inhibiting angiotensin-II induced aldosterone secretion; elevation in potassium may also be observed

ACE inhibitors also elicit renoprotective effects through vasodilation of renal arterioles

ACE inhibitors reduce cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction

Pharmacokinetics

Half-Life: 1.5-3 hr (perindopril);3-10 hr (perindoprilat):

Onset: 1-2 hr (peak response PO for HTN)

Peak Plasma Time: 1 hr (PO; perindopril); 3-7 hr (perindoprilat)

Therapeutic concentration range: 80-150 ng/mL

Renal clearance: 1.5 L/h (perindopril), 6-10 L/hr (perindoprilat total body: 21-31 L/h perindopril): 46 L/hr) (perindoprilat)

Excretion: Urine (75%)

Duration: 24 hr

Bioavailability: 75% (perindopril); 20-30% (perindoprilat)

Protein Bound: 60% (perindopril); 10-20% (perindoprilat)

Vd: 0.22 L/kg (perindopril); 0.16 L/kg (perindoprilat)

Metabolism: Liver (88 -96%)

Metabolites: Perindoprilat (active), glucuronide derivatives (inactive)

Dialyzable: HD: yes

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 [see WARNINGS AND PRECAUTIONS]
• Hypotension [see WARNINGS AND PRECAUTIONS]
• Neutropenia and agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Impaired renal function [see WARNINGS AND PRECAUTIONS]
• Hyperkalemia [see WARNINGS AND PRECAUTIONS]
• Cough [see WARNINGS AND PRECAUTIONS]

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.

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

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].

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.

Read the entire FDA prescribing information for Aceon (Perindopril Erbumine)

Applies to perindopril: oral tablet

Along with its needed effects, perindopril (the active ingredient contained in Aceon) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking perindopril:

• Body aches or pain
• chills
• cough
• difficulty breathing
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat
• unusual tiredness or weakness

• Abdominal or stomach pain
• bladder pain
• bloody or cloudy urine
• change in hearing
• chest pain
• cold or flu-like symptoms
• congestion
• difficult, burning, or painful urination
• dryness of the throat
• earache or pain in the ear
• ear drainage
• frequent urge to urinate
• hoarseness
• lower back or side pain
• swelling
• tender, swollen glands in the neck
• trouble with swallowing
• voice changes
• vomiting

• Blurred vision
• confusion
• decreased urination
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• irregular heartbeat
• muscle cramps or pain
• numbness, tingling, pain, or weakness in the hands or feet
• rapid breathing
• seizures
• sunken eyes
• sweating
• thirst
• trembling
• weakness and heaviness of the legs

Some side effects of perindopril may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• lack or loss of strength
• pain or tenderness around the eyes and cheekbones
• tightness of the chest

• Belching
• bloated
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• diarrhea
• difficulty moving
• discouragement
• excess air or gas in the stomach or intestines
• feeling sad or empty
• full feeling
• hearing loss
• injury
• irritability
• lack of appetite
• leg pain
• loss of interest or pleasure
• muscle aching, stiffness, tension, or tightness
• nausea
• neck pain
• nervousness
• pain, swelling, or redness in the joints
• passing gas
• rash
• sleepiness or unusual drowsiness
• stomach discomfort or upset
• swollen joints
• trouble concentrating
• trouble sleeping

Applies to perindopril: oral tablet

General

The most common adverse events were cough, dizziness, and back pain.[Ref]

Respiratory

Very common (10% or more): Cough (up to 12%)
Common (1% to 10%): Dyspnea, epistaxis
Uncommon (0.1% to 1%): Bronchospasm
Very rare (less than 0.01%): Eosinophilic pneumonia, rhinitis[Ref]

Nervous system

Common (1% to 10%): Dizziness, headache, paresthesia, vertigo, tinnitus, dysgeusia, drowsiness
Uncommon (0.1% to 1%): Somnolence, syncope
Very rare (less than 0.01%): Stroke[Ref]

Gastrointestinal

Common (1% to 10%): Abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting
Uncommon (0.1% to 1%): Dry mouth
Very rare (less than 0.01%): Pancreatitis
Postmarketing reports: Acute pancreatitis[Ref]

Cardiovascular

Common (1% to 10%): Hypotension, palpitations, vasculitis, flushing, impaired peripheral circulation
Uncommon (0.1% to 1%): Tachycardia
Rare (0.01% to 0.1%): Sudden cardiac arrest
Very rare (less than 0.01%): Angina pectoris, arrhythmia, myocardial infarction[Ref]

Dermatologic

Common (1% to 10%): Pruritus, rash
Uncommon (0.1% to 1%): Urticaria, angioedema, photosensitivity reactions, pemphigoid, hyperhidrosis, eczema, sweating
Very rare (less than 0.01%): Erythema multiforme
Postmarketing reports: Bullous pemphigoid, pemphigus, psoriasis, exfoliative dermatitis[Ref]

Other

Common (1% to 10%): Asthenia, discomfort on exertion
Uncommon (0.1% to 1%): Chest pain, malaise, edema peripheral, pyrexia, fall, atypical chest pain
Postmarketing reports: Serositis[Ref]

Musculoskeletal

Common (1% to 10%): Muscle cramps, back pain
Uncommon (0.1% to 1%): Arthralgia, myalgia[Ref]

Hepatic

Common (1% to 10%): ALT increased
Uncommon (0.1% to 1%): AST increased
Rare (0.01% to 0.1%): Blood bilirubin increased, hepatic enzyme increased
Very rare (less than 0.01%): Hepatitis
Postmarketing reports: Hepatic failure, jaundice[Ref]

Ocular

Common (1% to 10%): Visual disturbances[Ref]

Renal

Uncommon (0.1% to 1%): Renal insufficiency, blood urea increased, blood creatinine increased
Very rare (less than 0.01%): Acute renal failure
Postmarketing reports: Nephritis[Ref]

Metabolic

Uncommon (0.1% to 1%): Hypoglycemia, hyperkalemia, hyponatremia
Postmarketing reports: Symptomatic hyponatremia[Ref]

Hematologic

Uncommon (0.1% to 1%): Eosinophilia, leukopenia/neutropenia
Very rare (less than 0.01%): Agranulocytosis or pancytopenia, hemoglobin decreased and hematocrit decreased, hemolytic anemia in patients with a congenital deficiency of glucose-6-phosphate dehydrogenase, thrombocytopenia, unexplained change in prothrombin ratio
Postmarketing reports: Anemia, leukocytosis, elevated erythrocyte sedimentation rate[Ref]

Psychiatric

Uncommon (0.1% to 1%): Mood disturbances, sleep disorder
Very rare (less than 0.01%): Confusion, depression, hallucinations[Ref]

Genitourinary

Uncommon (0.1% to 1%): Erectile dysfunction[Ref]

Immunologic

Postmarketing reports: Positive antinuclear antibody[Ref]

Some side effects of Aceon may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

LactMed Record Number

211

Last Revision Date

20170905

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.