PERINDOPRIL
DESCRIPTION:
USE IN PREGNANCY
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, COVERSYL should be discontinued as
soon as possible.
See WARNINGS: FETAL/NEONATAL MORBIDITY AND
MORTALITY).
COVERSYL (perindopril erbumine) 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(alpha)S,7(alpha)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.
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+ACU-
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.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION: COVERSYL (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 COVERSYL 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+ACU-
attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition
is about 60+ACU- 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+ADs- there is about 35+ACU- inhibition at 24 hours after
a 12 mg dose.
PHARMACOKINETICS: Oral administration of COVERSYL (perindopril erbumine) results in
its rapid absorption with peak plasma concentrations occurring at approximately
1 hour. The absolute oral bioavailability of perindopril is about 75+ACU-. Following
absorption, approximately 30 to 50+ACU- of systemically available perindopril is
hydrolyzed to its active metabolite, perindoprilat, which has a mean
bioavailability of about 25+ACU-. Peak plasma concentrations of perindoprilat are
attained 3 to 7 hours after perindopril administration. The presence of food in
the gastrointestinal tract does not affect the rate or extent of absorption of
perindopril but reduces bioavailability of perindoprilat by about 35+ACU-. (See
PRECAUTIONS: FOOD INTERACTIONS.)
With 4, 8 and 16 mg doses of COVERSYL, 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 1.0 hours. At very low plasma concentrations
of perindopril (+ADw-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+ACU- 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 COVERSYL. 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 2.0 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+ACU- of circulating perindopril is bound to plasma proteins, and
only 10 to 20+ACU- of perindoprilat is bound. Therefore, drug interactions mediated
through effects on protein binding are not anticipated.
At usual antihypertensive dosages, little radioactivity (+ADw-5+ACU- of the dose) was
distributed to the brain after administration of 14C- perindopril to rats.
Radioactivity was detectable in fetuses and in milk after administration of 14C-
perindopril to pregnant and lactating rats.
ELDERLY PATIENTS: Plasma concentrations of both perindopril and perindoprilat in
elderly patients (+AD4-70 yrs) are approximately twice those observed in younger
patients, reflecting both increased conversion of perindopril to perindoprilat
and decreased renal excretion of perindoprilat. See PRECAUTIONS: GERIATRIC USE.
HEART FAILURE PATIENTS: Perindoprilat clearance is reduced in congestive heart
failure patients, resulting in a 40+ACU- higher dose interval AUC. (See DOSAGE AND
ADMINISTRATION.)
PATIENTS WITH RENAL INSUFFICIENCY: With perindopril erbumine doses of 2 to 4 mg,
perindoprilat AUC increases with decreasing renal function. At creatinine
clearances of 30 to 80 mL/min, AUC is about double that of 100 mL/min. When
creatinine clearance drops below 30 mL/min, AUC increases more markedly.
In a limited number of patients studied, perindopril dialysis clearance ranged
from 41.7 to 76.7 mL/min (mean 52.0 mL/min). Perindoprilat dialysis clearance
ranged from 37.4 to 91.0 mL/min (mean 67.2 mL/min). (See DOSAGE AND
ADMINISTRATION.)
PATIENTS WITH HEPATIC INSUFFICIENCY: 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+ACU- higher
than those observed in healthy subjects or hypertensive patients with normal
liver function.
PHARMACODYNAMICS:
In placebo-controlled studies of perindopril monotherapy (2 to 16 mg o.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+ACU- 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 COVERSYL have not been carried out with
antihypertensive agents other than thiazides. Limited experience in controlled
and uncontrolled trials coadministering COVERSYL with a calcium channel blocker, a
loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic) do
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 angiotension system. A controlled
pharmacokinetic study has shown no effect on plasma digoxin concentrations when
coadministered with COVERSYL. (See PRECAUTIONS: DRUG INTERACTIONS.)
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 COVERSYL was not influenced by sex and it was less effective
in blacks than in nonblacks. In elderly patients ((+AD4-/+AD0-)60 years), the mean blood
pressure effect was somewhat smaller than in younger patients, although the
difference was not significant.
INDICATIONS AND USAGE:
COVERSYL (perindopril erbumine) is indicated for the treatment of patients with
essential hypertension. COVERSYL may be used alone or given with other classes of
antihypertensives, especially thiazide diuretics.
When using COVERSYL, 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 COVERSYL has a similar
potential. (See WARNINGS.)
In considering use of COVERSYL, 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: ANGIOEDEMA.)
CONTRAINDICATIONS:
COVERSYL (perindopril erbumine) is contraindicated in patients known to be
hypersensitive to this product or to any other ACE inhibitor. COVERSYL is also
contraindicated in patients with a history of angioedema related to previous
treatment with an ACE inhibitor.
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 COVERSYL) may be subject to a variety
of adverse reactions, some of them serious.
ANGIOEDEMA: Angioedema involving the face, extremities, lips, tongue, glottis
and/or larynx has been reported in patients treated with ACE inhibitors,
including COVERSYL (perindopril erbumine) (0.1+ACU- of patients treated with COVERSYL in
U.S. clinical trials). In such cases, COVERSYL should be promptly discontinued and
the patient carefully observed until the swelling disappears. In instances where
swelling has been confined to the face and lips, the condition has generally
resolved without treatment, although antihistamines have been useful in
relieving symptoms. Angioedema associated with involvement of the tongue,
glottis or larynx, may be fatal due to airway obstruction. Appropriate therapy,
such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), should be
promptly administered. Patients with a history of angioedema unrelated to ACE
inhibitor therapy may be at increased risk of angioedema while receiving an ACE
inhibitor.
ANAPHYLACTOID REACTIONS DURING DESENSITIZATION: Two patients undergoing
desensitizing treatment with hymenoptera venom while receiving ACE inhibitors
sustained life-threatening anaphylactoid reactions. In the same patients, these
reactions were avoided when ACE inhibitors were temporarily withheld, but they
reappeared upon inadvertent rechallenge.
ANAPHYLACTOID REACTIONS DURING MEMBRANE EXPOSURE: Anaphylactoid reactions have
been reported in patients dialyzed with high-flux membranes and treated
concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been
reported in patients undergoing low-density lipoprotein apheresis with dextran
sulfate absorption.
HYPOTENSION: Like other ACE inhibitors, COVERSYL can cause symptomatic hypotension.
COVERSYL has been associated with hypotension in 0.3+ACU- of uncomplicated hypertensive
patients in U.S. placebo-controlled trials. Symptoms related to orthostatic
hypotension were reported in another 0.8+ACU- of patients.
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 COVERSYL. (See DOSAGE AND ADMINISTRATION.)
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, COVERSYL 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 COVERSYL 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. COVERSYL treatment can usually be continued following
restoration of volume and blood pressure.
NEUTROPENIA/AGRANULOCYTOSIS: Another ACE inhibitor, captopril, has been shown to
cause agranulocytosis and bone marrow depression, rarely in uncomplicated
patients but more frequently in patients with renal impairment, especially
patients with a collagen vascular disease such as systemic lupus erythematosus
or scleroderma. Available data from clinical trials of COVERSYL are insufficient to
show whether COVERSYL causes agranulocytosis at similar rates.
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+ADs- oligohydramnios in this setting has been
associated with fetal limb contractures, craniofacial deformation and
hypoplastic lung development. Prematurity, intrauterine growth retardation and
patent ductus arteriosus have also been reported, although it is not clear
whether these occurrences were due to the ACE- inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-
inhibitor exposure that has been limited to the first trimester. Mothers whose
embryos and fetuses are exposed to ACE inhibitors only during the first
trimester should be so informed. Nonetheless, when patients become pregnant,
physicians should make every effort to discontinue the use of COVERSYL 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, COVERSYL 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 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 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 cynomologous monkeys. On a mg/m(squared) 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.
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.
PRECAUTIONS:
GENERAL: IMPAIRED RENAL FUNCTION: As a consequence of inhibiting the renin-
angiotensin- aldosterone system, changes in renal function may be anticipated in
susceptible individuals.
HYPERTENSIVE PATIENTS WITH CONGESTIVE HEART FAILURE: 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
COVERSYL, may be associated with oliguria and/or progressive azotemia, and rarely
with acute renal failure and/or death.
HYPERTENSIVE PATIENTS WITH RENAL ARTERY STENOSIS: In hypertensive patients with
unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen
and serum creatinine may occur. Experience with ACE inhibitors suggests that
these increases are usually reversible upon discontinuation of the drug. In such
patients, renal function should be monitored during the first few weeks of
therapy.
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 COVERSYL, 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 DOSAGE AND ADMINISTRATION.)
HYPERKALEMIA: Elevations of serum potassium have been observed in some patients
treated with ACE inhibitors, including COVERSYL. In U.S. controlled clinical
trials, 1.4+ACU- of the patients receiving COVERSYL and 2.3+ACU- of patients receiving
placebo showed increased serum potassium levels to greater than 5.7 mEq/L. 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. Drugs associated with increases in serum
potassium should be used cautiously, if at all, with COVERSYL. (See DRUG
INTERACTIONS.)
COUGH: Presumably due to the inhibition of the degradation of endogenous
bradykinin, persistent nonproductive cough has been reported with all ACE
inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-
induced cough should be considered in the differential diagnosis of cough. In
controlled trials with perindopril, cough was present in 12+ACU- of perindopril
patients and 4.5+ACU- of patients given placebo.
SURGERY/ANESTHESIA: In patients undergoing surgery or during anesthesia with
agents that produce hypotension, COVERSYL 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.
INFORMATION FOR PATIENTS: ANGIOEDEMA: Angioedema, including laryngeal edema, can
occur with ACE inhibitor therapy, especially following the first dose. Patients
should be told to report immediately signs or symptoms suggesting angioedema
(swelling of face, extremities, eyes, lips, tongue, hoarseness or difficulty in
swallowing or breathing) and to take no more drug before consulting a physician.
SYMPTOMATIC HYPOTENSION: As with any antihypertensive therapy, patients should
be cautioned that lightheadedness can occur, especially during the first few
days of therapy and that it should be reported promptly. Patients should be told
that if fainting occurs, COVERSYL should be discontinued and a physician consulted.
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.
HYPERKALEMIA: Patients should be advised not to use potassium supplements or
salt substitutes containing potassium without a physician's advice.
NEUTROPENIA: Patients should be told to report promptly any indication of
infection (E.G., sore throat, fever) which could be a sign of neutropenia.
PREGNANCY: Female patients of childbearing age should be told about the
consequences of second and third trimester exposure to ACE inhibitors, and they
should also be told that these consequences do not appear to have resulted from
intrauterine ACE-inhibitor exposure that has been limited to the first
trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
DRUG INTERACTIONS: DIURETICS: Patients on diuretics, and especially those
started recently, may occasionally experience an excessive reduction of blood
pressure after initiation of COVERSYL therapy. The possibility of hypotensive
effects can be minimized by either discontinuing the diuretic or increasing the
salt intake prior to initiation of treatment with perindopril. If diuretics
cannot be interrupted, close medical supervision should be provided with the
first dose of COVERSYL, for at least two hours and until blood pressure has
stabilized for another hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
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: COVERSYL 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, they
should be given with caution and the patient's serum potassium should be
monitored frequently.
LITHIUM: Increased serum lithium and symptoms of lithium toxicity have been
reported in patients receiving concomitant lithium and ACE inhibitor therapy.
These drugs should be coadministered with caution and frequent monitoring of
serum lithium concentration is recommended. Use of a diuretic may further
increase the risk of lithium toxicity.
DIGOXIN: A controlled pharmacokinetic study has shown no effect on plasma
digoxin concentrations when coadministered with COVERSYL, 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. Coadministration of both drugs should proceed with caution.
FOOD INTERACTION: Oral administration of COVERSYL 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+ACU-, resulting in a
reduction in the plasma ACE inhibition curve of approximately 20+ACU-, probably
clinically insignificant. In clinical trials, perindopril was generally
administered in a non-fasting state.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: CARCINOGENESIS: 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/m(squared)) the maximum proposed clinical doses (16 mg/day) for 104 weeks.
MUTAGENESIS: No genotoxic potential was detected for COVERSYL, 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/m(squared)) the proposed maximum clinical dosage of COVERSYL during the period
of spermatogenesis in males or oogenesis and gestation in females.
PREGNANCY: Pregnancy Categories C (first trimester) and D (second and third
trimesters). (See WARNINGS: FETAL/NEONATAL MORBIDITY AND MORTALITY.)
NURSING MOTHERS: Milk of lactating rats contained radioactivity following
administration 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 COVERSYL is given to nursing mothers.
PEDIATRIC USE: Safety and effectiveness of COVERSYL 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. Experience with COVERSYL in elderly
patients at daily doses exceeding 8 mg is limited.
DRUG INTERACTIONS:
DIURETICS: Patients on diuretics, and especially those started recently, may
occasionally experience an excessive reduction of blood pressure after
initiation of COVERSYL therapy. The possibility of hypotensive effects can be
minimized by either discontinuing the diuretic or increasing the salt intake
prior to initiation of treatment with perindopril. If diuretics cannot be
interrupted, close medical supervision should be provided with the first dose of
COVERSYL, for at least two hours and until blood pressure has stabilized for
another hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
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: COVERSYL 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, they
should be given with caution and the patient's serum potassium should be
monitored frequently.
LITHIUM: Increased serum lithium and symptoms of lithium toxicity have been
reported in patients receiving concomitant lithium and ACE inhibitor therapy.
These drugs should be coadministered with caution and frequent monitoring of
serum lithium concentration is recommended. Use of a diuretic may further
increase the risk of lithium toxicity.
DIGOXIN: A controlled pharmacokinetic study has shown no effect on plasma
digoxin concentrations when coadministered with COVERSYL, 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. Coadministration of both drugs should proceed with caution.
FOOD INTERACTION: Oral administration of COVERSYL 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+ACU-, resulting in a
reduction in the plasma ACE inhibition curve of approximately 20+ACU-, probably
clinically insignificant. In clinical trials, perindopril was generally
administered in a non-fasting state.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
COVERSYL (perindopril erbumine) has been evaluated for safety in approximately
3,400 patients with hypertension in U.S. and foreign clinical trials. COVERSYL 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+ACU-) than in perindopril patients (8.2+ACU-), the incidence
appeared to increase with an increase in perindopril dose.
The data presented here are based on results from the 1,417 COVERSYL-treated
patients who participated in the U.S. clinical trials. Over 220 of these
patients were treated with COVERSYL 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+ACU- in patients treated
with COVERSYL and 6.7+ACU- 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 COVERSYL and in those
treated with placebo (approximately 75+ACU- in each group). Adverse events that
occurred in 1+ACU- or greater of the patients and that were more common for
perindopril than placebo by at least 1+ACU- (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.
FREQUENCY OF ADVERSE EVENTS (+ACU-)
ALL ADVERSE EVENTS POSSIBLY-OR PROBABLY-
RELATED ADVERSE EVENTS
Perindopril Placebo Perindopril Placebo
n+AD0-789 n+AD0-223 n+AD0-789 n+AD0-223
Cough 12.0 4.5 6.0 1.8
Back Pain 5.8 3.1 0.0 0.0
Sinusitis 5.2 3.6 0.6 0.0
Viral Infection 3.4 1.6 0.3 0.0
Upper Extremity Pain 2.8 1.4 0.2 0.0
Hypertonia 2.7 1.4 0.2 0.0
Dyspepsia 1.9 0.9 0.3 0.0
Fever 1.5 0.5 0.3 0.0
Proteinuria 1.5 0.5 1.0 0.5
Ear Infection 1.3 0.0 0.0 0.0
Palpitation 1.1 0.0 0.9 0.0
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Of these, cough was the reason for withdrawal in 1.3+ACU- of perindopril and 0.4+ACU- of
placebo patients. While dizziness was not reported more frequently in the
perindopril group (8.2+ACU-) than in the placebo group (8.5+ACU-), it was clearly
increased with dose, suggesting a causal relationship with perindopril. Other
commonly reported complaints (1+ACU- or greater), regardless of causality include:
headache (23.8+ACU-), upper respiratory infection (8.6+ACU-), asthenia (7.9+ACU-), rhinitis
(4.8+ACU-), low extremity pain (4.7+ACU-), diarrhea (4.3+ACU-), edema (3.9+ACU-), pharyngitis
(3.3+ACU-), urinary tract infection (2.8+ACU-), abdominal pain (2.7+ACU-), sleep disorder
(2.5+ACU-), chest pain (2.4+ACU-), injury, paresthesia, nausea, rash (each 2.3+ACU-),
seasonal allergy, depression (each 2.0+ACU-), abnormal ECG (1.8+ACU-), ALT increase
(1.7+ACU-), tinnitus, vomiting (each 1.5+ACU-), neck pain, male sexual dysfunction (each
1.4+ACU-), triglyceride increase, somnolence (each 1.3+ACU-), joint pain, nervousness,
myalgia, menstrual disorder (each 1.1+ACU-), flatulence and arthritis (each 1.0+ACU-),
but none of those was more frequent by at least 1+ACU- on perindopril, than on
placebo. Depending on the specific adverse event, approximately 30 to 70+ACU- of the
common complaints were considered possibly or probably related to treatment.
Below is a list (by body system) of adverse experiences reported in 0.3 to 1+ACU- of
patients in U.S. placebo-controlled studies without regard to attribution to
therapy. Less frequent but medically important adverse events are also included+ADs-
the incidence of these events are given in parentheses.
BODY AS A WHOLE: malaise, pain, cold/hot sensation, chills, fluid retention,
orthostatic symptoms, anaphylactic reaction, facial edema, angioedema (0.1+ACU-)
GASTROINTESTINAL: constipation, dry mouth, dry mucous membrane, appetite
increased, gastroenteritis
RESPIRATORY: posterior nasal drip, bronchitis, rhinorrhea, throat disorder,
dyspnea, sneezing, epistaxis, hoarseness, pulmonary fibrosis (+ADw-0.1+ACU-)
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+ACU-)
PSYCHIATRIC: anxiety, psychosexual disorder
DERMATOLOGY: sweating, skin infection, tinea, pruritus, dry skin, erythema,
fever blisters, purpura (0.1+ACU-)
SPECIAL SENSES: conjunctivitis, earache
LABORATORY: potassium decrease, uric acid increase, alkaline phosphatase
increase, cholesterol increase, AST increase, creatinine increase, hematuria,
glucose increase
When COVERSYL was given concomitantly with thiazide diuretics, adverse events were
generally reported at the same rate as those for COVERSYL 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).
POTENTIAL ADVERSE EFFECTS REPORTED WITH ACE INHIBITORS: Other medically
important adverse effects reported with other available ACE inhibitors 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 pemphigus, exfoliative
dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis,
serositis, myalgia, fever, rash or other dermatologic manifestations, a positive
ANA, leukocytosis, eosinophilia or an elevated ESR. Many of these adverse
effects have also been reported for perindopril.
FETAL/NEONATAL MORBIDITY AND MORTALITY: See WARNINGS: FETAL/NEONATAL MORBIDITY
AND MORTALITY).
CLINICAL LABORATORY TEST FINDINGS: 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.
HYPERKALEMIA: In clinical trials, 1.4+ACU- of the patients receiving COVERSYL and 2.3+ACU-
of the patients receiving placebo showed serum potassium levels greater than 5.7
mEq/L. (See PRECAUTIONS.)
BUN/SERUM CREATININE ELEVATIONS: Elevations, usually transient and minor, of BUN
or serum creatinine have been observed. In placebo- controlled clinical trials,
the proportion of patients experiencing increases in serum creatinine were
similar in the COVERSYL and placebo treatment groups. Rapid reduction of long-
standing or markedly elevated blood pressure by any antihypertensive therapy can
result in decreases in the glomerular filtration rate and, in turn, lead to
increases in BUN or serum creatinine. (See PRECAUTIONS.)
HEMATOLOGY: Small decreases in hemoglobin and hematocrit occur frequently in
hypertensive patients treated with COVERSYL, 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+ACU- of patients in U.S. clinical trials. (See WARNINGS.)
LIVER FUNCTION TESTS: Elevations in ALT (1.6+ACU- COVERSYL vs 0.9+ACU- placebo) and AST
(0.5+ACU- COVERSYL vs 0.4+ACU- placebo) have been observed in U.S. placebo- controlled
clinical trials. The elevations were generally mild and transient and resolved
after discontinuation of therapy.
OVERDOSAGE:
In animals, doses of perindopril up to 2500 mg/kg in mice, 3000 mg/kg in rats
and 1600 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.
DOSAGE AND ADMINISTRATION:
USE IN UNCOMPLICATED HYPERTENSIVE PATIENTS: In patients with essential
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. The usual maintenance dose range
is 4 to 8 mg administered as a single daily dose. COVERSYL may also be administered
in two divided doses. When once-daily dosing was compared to twice- daily dosing
in clinical studies, the B.I.D. regimen was generally slightly superior, but not
by more than about 0.5 to 1.0 mm Hg.
USE IN THE ELDERLY PATIENTS: As in younger patients, the recommended initial
dosages of COVERSYL for the elderly (+AD4-65 years) is 4 mg daily in one or in two
divided doses. The daily dosage may be titrated upward until blood pressure,
when measured just before the next dose, is controlled, but experience with
COVERSYL is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg
should be administered with caution and under close medical supervision. (See
PRECAUTIONS: GERIATRIC USE).)
USE WITH CONCOMITANT DIURETICS: If blood pressure is not adequately controlled
with perindopril alone, a diuretic may be added. In patients currently being
treated with a diuretic, symptomatic hypotension occasionally can occur
following the initial dose of perindopril. To reduce likelihood of such
reaction, the diuretic should, if possible, be discontinued 2 to 3 days prior to
beginning of COVERSYL therapy. (See WARNINGS.) Then, if blood pressure is not
controlled with COVERSYL alone, the diuretic should be resumed.
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 WARNINGS and PRECAUTIONS: DRUG INTERACTIONS.)
USE IN PATIENTS WITH IMPAIRED RENAL FUNCTION: 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 +ADw-30 mL/min), safety and efficacy of COVERSYL
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.
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