Aceon Information
Aceon (Perindopril)
Aceon (Perindopril)
Aceon (Perindopril) Description
Aceon (Perindopril) ® (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 CHNOCHN. 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 by hydrolysis of the ester group
to form perindoprilat, the biologically active metabolite.
Aceon (Perindopril) ® 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.
Aceon (Perindopril) Clinical Pharmacology
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 (Perindopril) ® Tablets 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 nonblacks, a finding consistent with previous experience of
other ACE inhibitors.
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 ID 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.
With 4, 8 and 16 mg doses of Aceon (Perindopril) ® Tablets, Cmax and AUC of perindopril and
perindoprilat increase in a linear and dose-proportional manner following both
single oral dosing and at steady state during a once-a-day multiple dosing
regimen.
Perindopril exhibits multiexponential pharmacokinetics following oral
administration. The mean half-life of perindopril associated with most of its
elimination is approximately 0.8 to 1 hours. At very low plasma concentrations
of perindopril (<3 ng/mL), there is a prolonged terminal elimination
half-life, similar to that seen with other ACE inhibitors, that results from
slow dissociation of perindopril from plasma/tissue ACE binding sites.
Perindopril does not accumulate with a once-a-day multiple dosing regimen. Mean
total body clearance of perindopril is 219 to 362 mL/min and its mean renal
clearance is 23.3 to 28.6 mL/min.
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 multiexponential
pharmacokinetics following the oral administration of Aceon (Perindopril) ® Tablets. 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.
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.
At usual antihypertensive dosages, little radioactivity (<5% of the dose)
was distributed to the brain after administration of C-perindopril to rats.
Radioactivity was detectable in fetuses and in milk after administration of
C-perindopril to pregnant and lactating rats.
In a limited number of patients studied, perindopril dialysis clearance
ranged from 41.7 to 76.7 mL/min (mean 52 mL/min). Perindoprilat dialysis
clearance ranged from 37.4 to 91 mL/min (mean 67.2 mL/min). (See )
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 (). 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 ().
The outcome was similar across all predefined subgroups by age, underlying
disease or concomitant medication ().
In placebo-controlled studies of perindopril monotherapy (2 to 16
mg q.d.) in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had
little effect, but doses of 4 to 16 mg lowered blood pressure. The 8 and 16 mg
doses were indistinguishable, and both had a greater effect than the 4 mg dose.
The magnitude of the blood pressure effect was similar in the standing and
supine positions, generally about 1 mm Hg greater on standing. In these studies,
doses of 8 and 16 mg per day gave supine, trough blood pressure reductions of 9
to 15/5 to 6 mm Hg. When once-daily and twice-daily dosing were compared, the
B.I.D. regimen was generally slightly superior, but by not more than about 0.5
to 1 mm Hg. After 2 to 16 mg doses of perindopril, the trough mean systolic and
diastolic blood pressure effects were approximately equal to the peak effects
(measured 3 to 7 hours after dosing.). Trough effects were about 75 to 100% of
peak effects. When perindopril was given to patients receiving 25 mg HCTZ, it
had an added effect similar in magnitude to its effect as monotherapy, but 2 to
8 mg doses were approximately equal in effectiveness. In general, the effect of
perindopril occurred promptly, with effects increasing slightly over several
weeks.
In hemodynamic studies carried out in animal models of hypertension, blood
pressure reduction after perindopril administration was accompanied by a
reduction in peripheral arterial resistance and improved arterial wall
compliance. In studies carried out in patients with essential hypertension, the
reduction in blood pressure was accompanied by a reduction in peripheral
resistance with no significant changes in heart rate or glomerular filtration
rate. An increase in the compliance of large arteries was also observed,
suggesting a direct effect on arterial smooth muscle, consistent with the
results of animal studies.
Formal interaction studies of Aceon (Perindopril) ® Tablets have not been carried out with
antihypertensive agents other than thiazides. Limited experience in controlled
and uncontrolled trials coadministering Aceon (Perindopril) ® Tablets with a calcium channel
blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a
diuretic), does not suggest any unexpected interactions. In general, ACE
inhibitors have less than additive effects when given with beta-adrenergic
blockers, presumably because both work in part through the renin angiotensin
system. A controlled pharmacokinetic study has shown no effect on plasma digoxin
concentrations when coadministered with Aceon (Perindopril) ® Tablets. (See .)
In uncontrolled studies in patients with insulin-dependent diabetes,
perindopril did not appear to affect glycemic control. In long-term use, no
effect on urinary protein excretion was seen in these patients.
The effectiveness of Aceon (Perindopril) ® Tablets was not influenced by sex and it was less
effective in blacks than in nonblacks. In elderly patients (60 years), the mean
blood pressure effect was somewhat smaller than in younger patients, although
the difference was not significant.
Aceon (Perindopril) Indications And Usage
Aceon (Perindopril) ® (perindopril erbumine) Tablets is indicated in patients
with stable coronary artery disease to reduce the risk of cardiovascular
mortality or nonfatal myocardial infarction. Aceon (Perindopril) ® Tablets can be used with
conventional treatment for management of coronary artery disease, such as
antiplatelet, antihypertensive or lipid-lowering therapy.
Aceon (Perindopril) ® (perindopril erbumine) Tablets is indicated for the
treatment of patients with essential hypertension. Aceon (Perindopril) ® Tablets may be used
alone or given with other classes of antihypertensives, especially thiazide
diuretics.
When using Aceon (Perindopril) ® 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 (Perindopril) ®
Tablets has a similar potential. (See .)
In considering use of Aceon (Perindopril) ® 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 .)
Aceon (Perindopril) Contraindications
Aceon (Perindopril) ® (perindopril erbumine) Tablets is contraindicated in
patients known to be hypersensitive to this product or to any other ACE
inhibitor. Aceon (Perindopril) ® Tablets is also contraindicated in patients with a history of
angioedema related to previous treatment with an ACE inhibitor.
Aceon (Perindopril) Warnings
Symptomatic hypotension associated with the use of ACE inhibitors is more
likely to occur in patients who have been volume and/or salt-depleted, as a
result of prolonged diuretic therapy, dietary salt restriction, dialysis,
diarrhea or vomiting. Volume and/or salt depletion should be corrected before
initiating therapy with Aceon (Perindopril) ® Tablets. (See )
In patients with congestive heart failure, with or without associated renal
insufficiency, 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 such
an excessive fall in blood pressure could result in a myocardial infarction or a
cerebrovascular accident.
In patients at risk of excessive hypotension, Aceon (Perindopril) ® Tablets 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 (Perindopril) ®
Tablets 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 (Perindopril) ® Tablets treatment can usually be continued
following restoration of volume and blood pressure.
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 neurological malformations,
have been reported following exposure to ACE inhibitors during the first
trimester of pregnancy.
When patients become pregnant, physicians should make every effort to
discontinue the use of Aceon (Perindopril) ® Tablets 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) ® Tablets 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 physicians should be aware,
however, that oligohydramnios may not appear until after the fetus has sustained
irreversible injury.
Infants with histories of 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.
No teratogenic effects of perindopril were seen in studies of pregnant rats,
mice, rabbits and cynomolgus monkeys. On a mg/m basis,
the doses used in these studies were 6 times (in mice), 670 times (in rats), 50
times (in rabbits) and 17 times (in monkeys) the maximum recommended human dose
(assuming a 50 kg adult). On a mg/kg basis, these multiples are 60 times (in
mice), 3,750 times (in rats), 150 times (in rabbits) and 50 times (in monkeys)
the maximum recommended human dose.
Aceon (Perindopril) Precautions
Some hypertensive patients without apparent pre-existing renal vascular
disease have developed increases in blood urea nitrogen and serum creatinine,
usually minor and transient. These increases are more likely to occur in
patients treated concomitantly with a diuretic and in patients with pre-existing
renal impairment. Reduction of dosages of Aceon (Perindopril) ® Tablets, the diuretic or both
may be required. In some cases, discontinuation of either or both drugs may be
necessary.
Evaluation of hypertensive patients should always include an assessment of
renal function. (See )
All patients should be cautioned that inadequate fluid intake or excessive
perspiration, diarrhea or vomiting can lead to an excessive fall in blood
pressure in association with ACE inhibitor therapy.
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.
Perindopril should be used with caution when administered to elderly patients
who are at an increased risk for falls due to age, their underlying disease
and/or their concurrent use of medications(s) associated with falls. Falls and
fall-related events may be exacerbated by the central nervous system effects of
dizziness and syncope as well as the symptomatic hypotension, including
orthostatic, associated with perindopril. Experience with Aceon (Perindopril) ® Tablets in
elderly patients at daily doses exceeding 8 mg is limited.
Aceon (Perindopril) Adverse Reactions
Aceon (Perindopril) ® (perindopril erbumine) Tablets has been evaluated for
safety in approximately 3,400 patients with hypertension in U.S. and foreign
clinical trials. Aceon (Perindopril) ® 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 (Perindopril) ®
Tablets-treated patients who participated in the U.S. clinical trials. Over 220
of these patients were treated with Aceon (Perindopril) ® 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 (Perindopril) ® 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 (Perindopril) ® 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%), 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%), 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 list (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.
When Aceon (Perindopril) ® Tablets was given concomitantly with thiazide diuretics, adverse
events were generally reported at the same rate as those for Aceon (Perindopril) ® Tablets
alone, except for a higher incidence of abnormal laboratory findings known to be
related to treatment with thiazide diuretics alone (, 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.
Aceon (Perindopril) Overdosage
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 (, 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.
Aceon (Perindopril) Dosage And Administration
In patients with stable coronary artery disease, Aceon (Perindopril) ® 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 (Perindopril) ® 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.
If the diuretic cannot be discontinued, an initial dose of 2 to 4 mg daily in
one or in two divided doses should be used with careful medical supervision for
several hours and until blood pressure has stabilized. The dosage should then be
titrated as described above. (See and .)
After the first dose of Aceon (Perindopril) ® Tablets, the patient should be followed
closely for the first two weeks of treatment and whenever the dose of Aceon (Perindopril) ®
Tablets and/or diuretics is increased (See and .) In patients who are currently being treated with
a diuretic, symptomatic hypotension occasionally can occur following the initial
dose of Aceon (Perindopril) ® Tablets. To reduce the likelihood of hypotension, the dose of
diuretic, if possible, can be adjusted which may diminish the likelihood of
hypotension. The appearance of hypotension after the initial dose of Aceon (Perindopril) ®
Tablets does not preclude subsequent careful dose titration with the drug,
following effective management of the hypotension.
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 (Perindopril) ® 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.
Aceon (Perindopril) How Supplied
© 2008 Solvay Pharmaceuticals, Inc.
500063/500064 Rev Mar 2008
Aceon (Perindopril) Principal Display Panel
Aceon (Perindopril) ® (perindopril erbumine) Tablets
4 mg
Aceon (Perindopril) ® (perindopril erbumine) Tablets
8 mg
