RAMIPRIL
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, RAMACE should be discontinued
as soon as possible. See WARNINGS:
Fetal/neonatal morbidity and mortality.
Ramipril is a 2-aza-bicyclo (3.3.0)-octane- 3-carboxylic acid derivative. It is
a white, crystalline substance soluble in polar organic solvents and buffered
aqueous solutions. Ramipril melts between 105 deg C and 112 deg C.
The CAS Registry Number is 87333-19-5. Ramipril's chemical name is (2S,3aS,6aS)-
1((S)-N- ((S)-1-Carboxy- 3-phenylpropyl)alanyl)octahydrocyclopenta(b)pyrro le-2-
carboxylic acid, 1-ethyl ester.
Its empiric formula is C23H32N2O5, and its molecular weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl angiotensin
converting enzyme inhibitor. Ramipril is converted to ramiprilat by hepatic
cleavage of the ester group.
RAMACE (ramipril) is supplied as hard shell capsules for oral administration
containing 1.25 mg, 2.5 mg, 5 mg of ramipril.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Ramipril and ramiprilat inhibit angiotensin- converting enzyme (ACE) in human
subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the
conversion of angiotensin I to the vasoconstrictor substance, angiotensin II.
Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to
decreased vasopressor activity and to decreased aldosterone secretion. The
latter decrease may result in a small increase of serum potassium. In
hypertensive patients with normal renal function treated with RAMACE alone
for up to 56 weeks, approximately 4% of patients during the trial had an
abnormally high serum potassium and an increase from baseline greater than 0.75
mEq/L, and none of the patients had an abnormally low potassium and a decrease
from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of
patients treated with RAMACE and hydrochlorothiazide for up to 56 weeks had
abnormally high potassium values and an increase from baseline of 0.75 mEq/L or
greater, and approximately 2% had abnormally low values and decreases from
baseline of 0.75 mEq/L or greater. (See PRECAUTIONS.) Removal of angiotensin II
negative feedback on renin secretion leads to increased plasma renin activity.
The effect of ramipril on hypertension appears to result at least in part from
inhibition of both issue and circulating ACE activity, thereby reducing
angiotensin II formation in tissue and plasma.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether
increased levels of bradykinin, a potent vasodepressor peptide, play a role in
the therapeutic effects of RAMACE remains to be elucidated.
While the mechanism through which RAMACE lowers blood pressure is believed to
be primarily suppression of the renin-angiotensin-aldosterone system, RAMACE
has an antihypertensive effect even in patients with low-renin hypertension.
Although RAMACE was antihypertensive in all races studied, black hypertensive
patients (usually a low-renin hypertensive population) had a smaller average
response to monotherapy than non-black patients.
PHARMACOKINETICS AND METABOLISM
Following oral administration of RAMACE, peak plasma concentrations of
ramipril are reached within one hour. The extent of absorption is at least 50-
60% and is not significantly influenced by the presence of food in the GI tract,
although the rate of absorption is reduced.
In a trial in which subjects received RAMACE capsules or the contents of
identical capsules dissolved in water, dissolved in apple juice, or suspended in
apple sauce, serum ramiprilat levels were essentially unrelated to the use or
nonuse of the concomitant liquid or food.
Cleavage of the ester group (primarily in the liver) converts ramipril to its
active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat
are reached 2-4 hours after drug intake. The serum protein binding of ramipril
is about 73% and that of ramiprilat about 56%; In Vitro, these percentages are
independent of concentration over the range of 0.01 to 10 mcgm/mL.
Ramipril is almost completely metabolized to ramiprilat, which has about 6 times
the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the
diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of
which are inactive. After oral administration of ramipril, about 60% of the
parent drug and its metabolites are eliminated in the urine, and about 40% is
found in the feces. Drug recovered in the feces may represent both biliary
excretion of metabolites and/or unabsorbed drug, however the proportion of a
dose eliminated by the bile has not been determined. Less than 2% of the
administered dose is recovered in urine as unchanged ramipril.
Blood concentrations of ramipril and ramiprilat increase with increased dose,
but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however,
is dose-proportional over the 2.5-20 mg dose range. The absolute
bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively,
when 5 mg of oral ramipril was compared with the same dose of ramipril given
intravenously.
Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid
decline, apparent elimination phase, terminal elimination phase). The initial
rapid decline, which represents distribution of the drug into a large peripheral
compartment and subsequent binding to both plasma and tissue ACE, has a half-
life of 2-4 hours. Because of its potent binding to ACE and slow dissociation
from the enzyme, ramiprilat shows two elimination phases. The apparent
elimination phase corresponds to the clearance of free ramiprilat and has a
half-life of 9-18 hours. The terminal elimination phase has a prolonged half-
life (>50 hours) and probably represents the binding/dissociation kinetics of
the ramiprilat/ACE complex. It does not contribute to the accumulation of the
drug. After multiple daily doses of ramipril 5-10 mg, the half-life of
ramiprilat concentrations within the therapeutic range was 13-17 hours.
After once-daily dosing, steady-state plasma concentrations of ramiprilat are
reached by the fourth dose. Steady-state concentrations of ramiprilat are
somewhat higher than those seen after the first dose of RAMACE, especially at
low doses (2.5 mg), but the difference is clinically insignificant.
In patients with creatinine clearance less than 40 ml/min/1.73M(squared), peak
levels of ramiprilat are approximately doubled, and trough levels may be as much
as quintupled. In multiple- dose regimens, the total exposure to ramiprilat
(AUC) in these patients is 3-4 times as large as it is in patients with normal
renal function who receive similar doses.
The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced
in patients with impaired renal function. Compared to normal subjects, patients
with creatinine clearance less than 40 ml/min/1.73M(squared) had higher peak and
trough ramiprilat levels and slightly longer times to peak concentrations. (See
DOSAGE AND ADMINISTRATION.)
In patients with impaired liver function, the metabolism of ramipril to
ramiprilat appears to be slowed, possibly because of diminished activity of
hepatic esterases, and plasma ramipril levels in these patients are increased
about 3-fold. Peak concentrations of ramiprilat in these patients, however, are
not different from those seen in subjects with normal hepatic function, and the
effect of a given dose of plasma ACE activity does not vary with hepatic
function.
PHARMACODYNAMICS
Single doses of ramipril of 2.5-20 mg produce approximately 60-80% inhibition of
ACE activity 4 hours after dosing with approximately 40-60% inhibition after 24
hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE
activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition
of ACE activity remaining 24 hours after dosing. The more prolonged effect of
even small multiple doses presumably reflects saturation of ACE binding sites by
ramiprilat and relatively slow release from those sites.
PHARMACODYNAMICS AND CLINICAL EFFECTS
HYPERTENSION
Administration of RAMACE to patients with mild to moderate hypertension
results in a reduction of both supine and standing blood pressure to about the
same extent with no compensatory tachycardia. Symptomatic postural hypotension
is infrequent, although it can occur in patients who are salt- and/or volume-
depleted. (See WARNINGS.) Use of RAMACE in combination with thiazide
diuretics gives a blood pressure lowering effect greater than that seen with
either agent alone.
In single-dose studies, doses of 5-20 mg of RAMACE lowered blood pressure
within 1-2 hours, with peak reductions achieved 3-6 hours after dosing. The
antihypertensive effect of a single dose persisted for 24 hours. In longer term
(4-12 weeks) controlled studies, once-daily doses of 2.5-10 mg were similar in
their effect, lowering supine or standing systolic and diastolic blood pressures
24 hours after dosing by about 6/4 mm Hg more than placebo. In comparisons of
peak vs. trough effect, the trough effect represented about 50-60% of the peak
response. In a titration study comparing divided (bid) vs. qd treatment, the
divided regimen was superior, indicating that for some patients the
antihypertensive effect with once-daily dosing is not adequately maintained.
(See DOSAGE AND ADMINISTRATION).
In most trials, the antihypertensive effect of RAMACE increased during the
first several weeks of repeated measurements. The antihypertensive effect of
RAMACE has been shown to continue during long-term therapy for at least 2
years. Abrupt withdrawal of RAMACE has not resulted in a rapid increase in
blood pressure.
RAMACE has been compared with other ACE inhibitors, beta-blockers, and
thiazide diuretics. It was approximately as effective as other ACE inhibitors
and as atenolol. In both caucasians and blacks, hydrochlorothiazide (25 or 50
mg) was significantly more effective than ramipril.
Except for thiazides, no formal interaction studies of ramipril with other
antihypertensive agents have been carried out. Limited experience in controlled
and uncontrolled trials combining ramipril with a calcium channel blocker, a
loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic)
indicate no unusual drug-drug interactions. Other ACE inhibitors have had less
than additive effects with beta adrenergic blockers, presumably because both
drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.
RAMACE was less effective in blacks than in caucasians. The effectiveness of
RAMACE was not influenced by age, sex, or weight.
In a baseline controlled study of 10 patients with mild essential hypertension,
blood pressure reduction was accompanied by a 15% increase in renal blood flow.
In healthy volunteers, glomerular filtration rate was unchanged.
HEART FAILURE POST MYOCARDIAL INFARCTION
RAMACE was studied in the Acute Infarction Ramipril Efficacy (AIRE) trial.
This was a multinational (mainly European) 161-center, 2006-patient, double-
blind, randomized, parallel- group study comparing RAMACE to placebo in
stable patients, 2-9 days after an acute myocardial infarction (MI), who had
shown clinical signs of congestive heart failure (CHF) at any time after the MI.
Patients in severe (NYHA class IV) heart failure, patients with unstable angina,
patients with heart failure of congenital or valvular etiology, and patients
with contraindications to ACE inhibitors were all excluded. The majority of
patients had received thrombolytic therapy at the time of the index infarction,
and the average time between infarction and initiation of treatment was 5 days.
Patients randomized to ramipril treatment were given an initial dose of 2.5 mg
twice daily. If the initial regimen caused undue hypotension, the dose was
reduced to 1.25 mg, but in either event doses were titrated upward (as
tolerated) to a target regimen (achieved in 77% of patients randomized to
ramipril) of 5 mg twice daily. Patients were then followed for an average of 15
months (range 6-46).
The use of RAMACE was associated with a 27% reduction (p=0.002), in the risk
of death from any cause; about 90% of the deaths that occurred were
cardiovascular, mainly sudden death. The risks of progression to severe heart
failure and of CHF-related hospitalization were also reduced, by 23% (p=0.017)
and 26% (p=0.011), respectively. The benefits of RAMACE therapy were seen in
both genders, and they were not affected by the exact timing of the initiation
of therapy, but older patients may have had a greater benefit than those under
65. The benefits were seen in patients on, and not on, various concomitant
medications; at the time of randomization these included aspirin (about 80% of
patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers
(about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).
INDICATIONS AND USAGE:
HYPERTENSION
RAMACE is indicated for the treatment of hypertension. It may be used alone
or in combination with thiazide diuretics.
In using RAMACE, 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 show that RAMACE does not have a similar
risk. (See WARNINGS.)
In considering use of RAMACE, it should be noted that in controlled trials
ACE inhibitors have an effect on blood pressure that is less in black patients
than in non-blacks. In addition, ACE inhibitors (for which adequate data are
available) cause a higher rate of angioedema in black than in non-black
patients. (See WARNINGS, Angioedema.)
HEART FAILURE POST MYOCARDIAL INFARCTION
Ramipril is indicated in stable patients who have demonstrated clinical signs of
congestive heart failure within the first few days after sustaining acute
myocardial infarction. Administration of ramipril to such patients has been
shown to decrease the risk of death (principally cardiovascular death) and to
decrease the risks of failure-related hospitalization and progression to
severe/resistant heart failure. (See ACTIONS/CLINICAL PHARMACOLOGY, Heart
Failure post myocardial infarction for details and limitations of the survival
trial.)
CONTRAINDICATIONS:
RAMACE is contraindicated in patients who are hypersensitive to this product
and in patients with a history of angioedema related to previous treatment with
an angiotensin converting enzyme inhibitor.
WARNINGS:
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, RAMACE should be discontinued
as soon as possible. See WARNINGS:
Fetal/neonatal morbidity and mortality.
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 RAMACE) may be subject to a
variety of adverse reactions, some of them serious.
ANGIOEDEMA
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be
at increased risk of angioedema while receiving an ACE inhibitor. (See also
CONTRAINDICATIONS.)
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been
reported in patients treated with angiotensin converting enzyme inhibitors.
Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or
angioedema of the face, tongue, or glottis occurs, treatment with RAMACE
should be discontinued and appropriate therapy instituted immediately. Where
there is involvement of the tongue, glottis, or larynx, likely to cause airway
obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution
1:1,000 (0.3 ml to 0.5 ml) should be promptly administered. (See ADVERSE
REACTIONS.)
In a large U.S. postmarketing study, angioedema (defined as reports of angio,
face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) of black
patients and in 8/8680 (0.09%) of white patients. These rates were not different
statistically. 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
RAMACE can cause symptomatic hypotension, after either the initial dose or a
later dose when the dosage has been increased. Like other ACE inhibitors,
ramipril has been only rarely associated with hypotension in uncomplicated
hypertensive patients. Symptomatic hypotension is most 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
RAMACE.
In patients with congestive heart failure, with or without associated renal
insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may
be associated with oliguria or azotemia and, rarely, with acute renal failure
and death. In such patients, RAMACE therapy should be started under close
medical supervision; they should be followed closely for the first 2 weeks of
treatment and whenever the dose of ramipril or diuretic is increased.
If hypotension occurs, the patient should be placed in a supine position and, if
necessary, treated with intravenous infusion of physiological saline. RAMACE
treatment usually can be continued following restoration of blood pressure and
volume.
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.
NEUTROPENIA/AGRANULOCYTOSIS
Another angiotensin converting enzyme 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 if
they also have a collagen-vascular disease such as systemic lupus erythematosus
or scleroderma. Available data from clinical trials of ramipril are insufficient
to show that ramipril does not cause agranulocytosis at similar rates.
Monitoring of white blood cell counts should be considered in patients with
collagen-vascular disease, especially if the disease is associated with impaired
renal function.
FETAL/NEONATAL MORBIDITY AND MORTALITY
ACE inhibitors can cause fetal and neonatal morbidity and death when
administered to pregnant women. Several dozen cases have been reported in the
world literature. When pregnancy is detected, ACE inhibitors should be
discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy
has been associated with fetal and neonatal injury, including hypotension,
neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and
death. Oligohydramnios has also been reported, presumably resulting from
decreased fetal renal function; oligohydramnios in this setting has been
associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, 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 RAMACE 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
intraamniotic environment.
If oligohydramnios is observed, RAMACE should be discontinued unless it is
considered life- saving for the mother. Contraction stress testing (CST), a
nonstress 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.
RAMACE which crosses the placenta can 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 RAMACE were seen in studies of pregnant rats,
rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used
were up to approximately 400 times (in rats and monkeys) and 2 times (in
rabbits) the recommended human dose.
PRECAUTIONS:
IMPAIRED RENAL FUNCTION: As a consequence of inhibiting the renin-angiotensin-
aldosterone system, changes in renal function may be anticipated in susceptible
individuals. In patients with severe congestive heart failure whose renal
function may depend on the activity of the renin-angiotensin-aldosterone system,
treatment with angiotensin converting enzyme inhibitors, including RAMACE,
may be associated with oliguria and/or progressive azotemia and (rarely) with
acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis,
increases in blood urea nitrogen and serum creatinine may occur. Experience with
another angiotensin converting enzyme inhibitor suggests that these increases
are usually reversible upon discontinuation of RAMACE and/or diuretic
therapy. In such patients renal function should be monitored during the first
few weeks of therapy. Some hypertensive patients with no apparent pre-existing
renal vascular disease have developed increases in blood urea nitrogen and serum
creatinine, usually minor and transient, especially when RAMACE has been
given concomitantly with a diuretic. This is more likely to occur in patients
with pre-existing renal impairment. Dosage reduction of RAMACE and/or
discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal
function. (See DOSAGE AND ADMINISTRATION.)
HYPERKALEMIA: In clinical trials, hyperkalemia (serum potassium greater than
5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving
RAMACE (ramipril). In most cases, these were isolated values, which resolved
despite continued therapy. None of these patients was discontinued from the
trials because of hyperkalemia. Risk factors for the development of hyperkalemia
include renal insufficiency, diabetes mellitus, and the concomitant use of
potassium-sparing diuretics, potassium supplements, and/or potassium-containing
salt substitutes which should be used cautiously, if at all, with RAMACE.
(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.
IMPAIRED LIVER FUNCTION: Since ramipril is primarily metabolized by hepatic
esterases to its active moiety, ramiprilat, patients with impaired liver
function could develop markedly elevated plasma levels of ramipril. No formal
pharmacokinetic studies have been carried out in hypertensive patients with
impaired liver function.
SURGERY/ANESTHESIA: In patients undergoing surgery or during anesthesia with
agents that produce hypotension, ramipril may block angiotensin II formation
that would otherwise occur secondary to compensatory renin release. Hypotension
that occurs as a result of this mechanism can be corrected by volume expansion.
INFORMATION FOR PATIENTS
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.
ANGIOEDEMA: Angioedema, including laryngeal edema, can occur with treatment with
ACE inhibitors, especially following the first dose. Patients should be so
advised and told to report immediately any signs or symptoms suggesting
angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing)
and to take no more drug until they have consulted with the prescribing
physician.
SYMPTOMATIC HYPOTENSION: Patients should be cautioned that lightheadedness can
occur, especially during the first days of therapy, and it should be reported.
Patients should be told that if syncope occurs, RAMACE should be discontinued
until the physician has been 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, with the same consequences of lightheadedness and possible syncope.
HYPERKALEMIA: Patients should be told not to use salt substitutes containing
potassium without consulting their physician.
NEUTROPENIA: Patients should be told to promptly report any indication of
infection (e.g., sore throat, fever), which could be a sign of neutropenia.
DRUG INTERACTIONS
WITH DIURETICS: Patients on diuretics, especially those in whom diuretic
therapy was recently instituted, may occasionally experience an excessive
reduction of blood pressure after initiation of therapy with RAMACE. The
possibility of hypotensive effects with RAMACE can be minimized by either
discontinuing the diuretic or increasing the salt intake prior to initiation of
treatment with RAMACE. If this is not possible, the starting dose should be
reduced. (See DOSAGE AND ADMINISTRATION.)
WITH POTASSIUM SUPPLEMENTS AND POTASSIUM-SPARING DIURETICS: RAMACE can
attenuate potassium loss caused by thiazide diuretics. Potassium- sparing
diuretics (spironolactone, amiloride, triamterene, and others) or potassium
supplements 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.
WITH LITHIUM: Increased serum lithium levels and symptoms of lithium toxicity
have been reported in patients receiving ACE inhibitors during therapy with
lithium.These drugs should be coadministered with caution, and frequent
monitoring of serum lithium levels is recommended. If a diuretic is also used,
the risk of lithium toxicity may be increased.
OTHER: Neither RAMACE nor its metabolites have been found to interact with
food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin.
The combination of RAMACE and propranolol showed no adverse effects on
dynamic parameters (blood pressure and heart rate). The co-administration of
RAMACE and warfarin did not adversely affect the anticoagulant effects of the
latter drug. Additionally, co-administration of RAMACE with phenprocoumon did
not affect minimum phenprocoumon levels or interfere with the subjects' state of
anti-coagulation.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
No evidence of a tumorigenic effect was found when ramipril was given by gavage
to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to
18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are
about 200 times the maximum recommended human dose when compared on the basis of
body surface area.) No mutagenic activity was detected in the Ames test in
bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human
cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell
line. Several metabolites and degradation products of ramipril were also
negative in the Ames test. A study in rats with dosages as great as 500
mg/kg/day did not produce adverse effects on fertility.
PREGNANCY
Pregnancy Category C (first Trimester) And D (second And Third Trimesters). See
WARNINGS: Fetal/neonatal morbidity and mortality.
NURSING MOTHERS
Ingestion of single 10 mg oral dose of RAMACE resulted in undetectable
amounts of ramipril and its metabolites in breast milk. However, because
multiple doses may produce low milk concentrations that are not predictable from
single doses, women receiving RAMACE should not breast feed.
GERIATRIC USE
Of the total number of patients who received ramipril in US clinical studies of
RAMACE 11.0% were 65 and over while 0.2% were 75 and over. No overall
differences in effectiveness or safety were observed between these patients and
younger patients, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
One pharmacokinetic study conducted in hospitalized elderly patients indicated
that peak ramiprilat levels and area under the plasma concentration time curve
(AUC) for ramiprilat are higher in older patients.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
WITH DIURETICS: Patients on diuretics, especially those in whom diuretic
therapy was recently instituted, may occasionally experience an excessive
reduction of blood pressure after initiation of therapy with RAMACE. The
possibility of hypotensive effects with RAMACE can be minimized by either
discontinuing the diuretic or increasing the salt intake prior to initiation of
treatment with RAMACE. If this is not possible, the starting dose should be
reduced. (See DOSAGE AND ADMINISTRATION.)
WITH POTASSIUM SUPPLEMENTS AND POTASSIUM-SPARING DIURETICS: RAMACE can
attenuate potassium loss caused by thiazide diuretics. Potassium- sparing
diuretics (spironolactone, amiloride, triamterene, and others) or potassium
supplements 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.
WITH LITHIUM: Increased serum lithium levels and symptoms of lithium toxicity
have been reported in patients receiving ACE inhibitors during therapy with
lithium.These drugs should be coadministred with caution, and frequent
monitoring of serum lithium levels is recommended. If a diuretic is also used,
the risk of lithium toxicity may be increased.
OTHER: Neither RAMACE nor its metabolites have been found to interact with
food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin.
The combination of RAMACE and propranolol showed no adverse effects on
dynamic parameters (blood pressure and heart rate). The co-administration of
RAMACE and warfarin did not adversely affect the anticoagulant effects of the
latter drug. Additionally, co-administration of RAMACE with phenprocoumon did
not affect minimum phenprocoumon levels or interfere with the subjects' state of
anti-coagulation.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
HYPERTENSION
RAMACE has been evaluated for safety in over 4,000 patients with
hypertension; of these, 1,230 patients were studied in US controlled trials, and
1,107 were studied in foreign controlled trials. Almost 700 of these patients
were treated for at least one year. The overall incidence of reported adverse
events was similar in RAMACE and placebo patients. The most frequent clinical
side effects (possibly or probably related to study drug) reported by patients
receiving RAMACE in US placebo-controlled trials were: headache (5.4%),
"dizziness" (2.2%) and fatigue or asthenia (2.0%), but only the last was more
common in RAMACE patients than in patients given placebo. Generally, the side
effects were mild and transient, and there was no relation to total dosage
within the range of 1.25 to 20 mg. Discontinuation of therapy because of a side
effect was required in approximately 3% of US patients treated with RAMACE.
The most common reasons for discontinuation were: cough (1.0%), "dizziness"
(0.5%), and impotence (0.4%).
The side effects considered possibly or probably related to study drug that
occurred in US placebo-controlled trials in more than 1% of patients treated
with RAMACE are shown below.
PATIENTS IN US PLACEBO CONTROLLED STUDIES
Ramace Placebo
(N=651) (N=286)
n % n %
Headache 35 5.4 17 5.9
"Dizziness" 14 2.2 9 3.1
Asthenia (Fatigue) 13 2.0 2 0.7
Nausea/Vomiting 7 1.1 3 1.0
In placebo-controlled trials, there was also an excess of upper respiratory
infection and flu syndrome in the ramipril group. As these studies were carried
out before the relationship of cough to ACE inhibitors was recognized, some of
these events may represent ramipril-induced cough. In a later 1-year study,
increased cough was seen in almost 12% of ramipril patients, with about 4% of
these patients requiring discontinuation of treatment.
HEART FAILURE POST MYOCARDIAL INFARCTION
Adverse reactions (except laboratory abnormalities) considered possibly/probably
related to study drug that occurred in more than one percent of patients with
heart failure treated with RAMACE are shown below. The incidences represent
the experiences from the AIRE study. The follow-up time was between 6 and 46
months for this study.
PERCENTAGE OF PATIENTS WITH ADVERSE EVENTS
POSSIBLY/PROBABLY RELATED TO STUDY DRUG
PLACEBO-CONTROLLED (AIRE) MORTALITY STUDY
ADVERSE EVENT RAMIPRIL PLACEBO
(N=1004) (N=982)
Hypotension 10.7 4.7
Cough Increased 7.6 3.7
Dizziness 4.1 3.2
Angina Pectoris 2.9 2.0
Nausea 2.2 1.4
Postural Hypotension 2.2 1.4
Syncope 2.1 1.4
Heart Failure 2.0 2.2
Severe/Resistance
Heart Failure 2.0 3.0
Myocardial Infarct 1.7 1.7
Vomiting 1.6 0.5
Vertigo 1.5 0.7
Headache 1.2 0.8
Kidney Function 1.2 0.5
Abnormal Chest Pain 1.1 0.9
Diarrhea 1.1 0.4
Asthenia 0.3 0.8
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Other adverse experiences reported in controlled clinical trials (in less than
1% of ramipril patients), or rarer events seen in postmarketing experience,
include the following (in some, a causal relationship to drug use is uncertain):
BODY AS A WHOLE: Anaphylactoid reactions. (See WARNINGS.)
CARDIOVASCULAR: Symptomatic hypotension (reported in 0.5% of patients in US
trials) (See WARNINGS and PRECAUTIONS), syncope (not reported in US trials),
angina pectoris, arrhythmia, chest pain, palpitations, myocardial infarction,
and cerebrovascular events.
HEMATOLOGIC: Pancytopenia, hemolytic anemia and thrombocytopenia.
RENAL: Some hypertensive patients with no apparent pre-existing renal disease
have developed minor, usually transient, increases in blood urea nitrogen and
serum creatinine when taking RAMACE, particularly when RAMACE was given
concomitantly with a diuretic. (See WARNINGS.)
ANGIONEUROTIC EDEMA: Angioneurotic edema has been reported in 0.3% of patients
in US clinical trials. (See WARNINGS.)
COUGH: A tickling, dry, persistent, nonproductive cough has been reported with
the use of ACE inhibitors. Approximately 1% of patients treated with RAMACE
have required discontinuation because of cough. The cough disappears shortly
after discontinuation of treatment. (See PRECAUTIONS, Cough subsection.)
GASTROINTESTINAL Pancreatitis, abdominal pain (sometimes with enzyme changes
suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth,
dyspepsia, dysphagia, gastroenteritis, hepatitis, nausea, increased salivation,
taste disturbance, and vomiting.
DERMATOLOGIC: Apparent hypersensitivity reactions (manifested by urticaria,
pruritis, or rash, with or without fever), erythema multiforme, pemphigus,
photosensitivity, and purpura.
NEUROLOGIC AND PSYCHIATRIC: Anxiety, amnesia, convulsions, depression, hearing
loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence,
tinnitus, tremor, vertigo, and vision disturbances.
MISCELLANEOUS: As with other ACE inhibitors, a symptom complex has been
reported which may include a positive ANA, an elevated erythrocyte sedimentation
rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia,
photosensitivity, rash and other dermatologic manifestations.
Fetal/neonatal Morbidity And Mortality. See WARNINGS: Fetal/neonatal morbidity
and mortality.
OTHER: arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased
sweating, malaise, myalgia, and weight gain.
CLINICAL LABORATORY TEST FINDINGS:
CREATININE AND BLOOD UREA NITROGEN: Increases in creatinine levels occurred in
1.2% of patients receiving RAMACE alone, and in 1.5% of patients receiving
RAMACE and a diuretic. Increases in blood urea nitrogen levels occurred in
0.5% of patients receiving RAMACE alone and in 3% of patients receiving
RAMACE with a diuretic. None of these increases required discontinuation of
treatment. Increases in these laboratory values are more likely to occur in
patients with renal insufficiency or those pretreated with a diuretic and, based
on experience with other ACE inhibitors, would be expected to be especially
likely in patients with renal artery stenosis. (See WARNINGS and PRECAUTIONS.)
Since ramipril decreases aldosterone secretion, elevation of serum potassium can
occur. Potassium supplements and potassium-sparing diuretics should be given
with caution, and the patient's serum potassium should be monitored frequently.
(See WARNINGS and PRECAUTIONS.)
HEMOGLOBIN AND HEMATOCRIT: Decreases in hemoglobin or hematocrit (a low value
and a decrease of 5 g/dl or 5% respectively) were rare, occurring in 0.4% of
patients receiving RAMACE alone and in 1.5% of patients receiving RAMACE
plus a diuretic. No US patients discontinued treatment because of decreases in
hemoglobin or hematocrit.
OTHER (CAUSAL RELATIONSHIPS UNKNOWN): Clinically important changes in standard
laboratory tests were rarely associated with RAMACE administration.
Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have
been reported, as have cases of hyponatremia and scattered incidents of
leukopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of
patients discontinued treatment for laboratory abnormalities: all of these were
cases of proteinuria or abnormal liver-function tests.
OVERDOSAGE:
Single oral doses in rats and mice of 10-11 g/kg resulted in significant
lethality. In dogs, oral doses as high as 1 g/kg induced only mild
gastrointestinal distress. Limited data on human overdosage are available. The
most likely clinical manifestations would be symptoms attributable to
hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are
not widely available, and such determinations have, in any event, no established
role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to
change the pH of the urine) that might accelerate elimination of ramipril and
its metabolites. Similarly, it is not known which, if any, of these substances
can be usefully removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the
setting of ramipril overdose, but angiotensin II is essentially unavailable
outside of scattered research facilities. Because the hypotensive effect of
ramipril is achieved through vasodilation and effective hypovolemia, it is
reasonable to treat ramipril overdose by infusion of normal saline solution.
DOSAGE AND ADMINISTRATION:
HYPERTENSION
The recommended initial dose for patients not receiving a diuretic is 2.5 mg
once a day. Dosage should be adjusted according to the blood pressure response.
The usual maintenance dosage range is 2.5 to 20 mg per day administered as a
single dose or in two equally divided doses. In some patients treated once
daily, the antihypertensive effect may diminish toward the end of the dosing
interval. In such patients, an increase in dosage or twice daily administration
should be considered. If blood pressure is not controlled with RAMACE alone,
a diuretic can be added.
HEART FAILURE POST MYOCARDIAL INFARCTION
For the treatment of post-infarction patients who have shown signs of congestive
failure, the recommended starting dose of RAMACE is 2.5 mg twice daily. A
patient who becomes hypotensive at this dose may be switched to 1.25 mg twice
daily, but all patients should then be titrated (as tolerated) toward a target
dose of 5 mg twice daily.
After the initial dose of RAMACE, the patient should be observed under
medical supervision for at least two hours and until blood pressure has
stabilized for at least an additional hour. (See WARNINGS and PRECAUTIONS, Drug
Interactions.) If possible, the dose of any concomitant diuretic should be
reduced which may diminish the likelihood of hypotension. The appearance of
hypotension after the initial dose of RAMACE does not preclude subsequent
careful dose titration with the drug, following effective management of the
hypotension.
The RAMACE Capsule is usually swallowed whole. The RAMACE Capsule can also
be opened and the contents sprinkled on a small amount (about 4 oz.) of apple
sauce or mixed in 4 oz. (120 ml) of water or apple juice. To be sure that
ramipril is not lost when such a mixture is used, the mixture should be consumed
in its entirety. The described mixtures can be pre-prepared and stored for up to
24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of RAMACE with potassium supplements, potassium
salt substitutes, or potassium-sparing diuretics can lead to increases of serum
potassium (See PRECAUTIONS.)
In patients who are currently being treated with a diuretic, symptomatic
hypotension occasionally can occur following the initial dose of RAMACE. To
reduce the likelihood of hypotension, the diuretic should, if possible, be
discontinued two to three days prior to beginning therapy with RAMACE. (See
WARNINGS.) Then, if blood pressure is not controlled with RAMACE alone,
diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 1.25 mg RAMACE
should be used to avoid excess hypotension.
DOSAGE ADJUSTMENT IN RENAL IMPAIRMENT
In patients with creatinine clearance <40 ml/min/1.73m(squared) (serum
creatinine approximately >2.5 mg/dl) doses only 25% of those normally used
should be expected to induce full therapeutic levels of ramiprilat. (See
ACTIONS/CLINICAL PHARMACOLOGY.)
HYPERTENSION: For patients with hypertension and renal impairment, the
recommended initial dose is 1.25 mg RAMACE once daily. Dosage may be titrated
upward until blood pressure is controlled or to a maximum total daily dose of 5
mg.
HEART FAILURE POST MYOCARDIAL INFARCTION: For patients with heart failure and
renal impairment, the recommended initial dose is 1.25 mg RAMACE once daily.
The dose may be increased to 1.25 mg b.i.d. and up to a maximum dose of 2.5 mg
b.i.d. depending upon clinical response and tolerability.
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Reduction of cardiovascular events and
microvascular complications in diabetes with ACE
inhibitor treatment: HOPE and MICRO-HOPE
Hertzel C. Gerstein*
McMaster University, Department of
Medicine, Hamilton, Ontario,
Canada
Summary
The Heart Outcomes Prevention Evaluation (HOPE) study, an international
randomized trial, was designed to evaluate the effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril and vitamin E in patients at high risk for cardiovascular events. The study did not detect any cardiovascular benefit or harm using vitamin E. Results for the vitamin E arm are not discussed here. Of 9541 patients, 3577 with diabetes received either ramipril (10 mg) or placebo. Among these patients, ramipril use was associated with a significant 25% reduction in risk for the composite endpoint of myocardial infarcrion (MI), stroke, or cardiovascular death after a median follow-up
period of 4,5 years. This benefit was independent of any blood pressure-lowering effect. The Microalbummuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO-HOPE) substudy in this patient population showed that ramipril treatment was associated with a decreased risk of development of overt nephropathy. Use of a composite measure of microvascular complications also suggested a protective effect of ramipril treatment. An interesting finding in the HOPE study is that ramipril treatment was associated with it significant 34% reduction in new diagnoses of diabetes. The possibility that ACE inhibitor treatment with ramipril may prevent new diabetes in non-diabetic patients at high risk of the disease is to be examined prospectively in the Diabetes Reduction Assessment with ramipril and rosiglitazone (DREAM)
trial.