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USE IN PREGNANCY
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
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, PRINIVIL should be
discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
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PRINIVIL* (Lisinopril), a synthetic peptide derivative, is an oral long-acting angiotensin
converting enzyme inhibitor. Lisinopril is chemically described as (S)-1-[N2-(1-carboxy-3-
phenylpropyl-L-lysyl]-L-proline dehydrate. Its empirical formula is C21H31N3O5 · 2H2O and its
structural formula is:
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is
soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg tablets for oral administration.
In addition to the active ingredient lisinopril, each tablet contains the following inactive
ingredients: calcium phosphate, mannitol, magnesium stearate, and starch. The 10 mg, 20 mg
and 40 mg tablets also contain iron oxide.
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Mechanism of Action
Lisinopril inhibits 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. The beneficial effects of lisinopril in hypertension and heart failure appear to result
primarily from suppression of the renin-angiotensin-aldosterone system. 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 PRINIVIL alone for
up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however,
approximately 15 percent of patients had increases greater than 0.5 mEq/L and approximately
six percent had a decrease greater than 0.5 mEq/L. In the same study, patients treated with
PRINIVIL and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium
of 0.1 mEq/L; approximately 4 percent of patients had increases greater than 0.5 mEq/L and
approximately 12 percent had a decrease greater than 0.5 mEq/L, (See PRECAUTIONS.)
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
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 PRINIVIL
remains to be elucidated.
While the mechanism through which PRINIVIL lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive even in
patients with low-renin hypertension. Although PRINIVIL 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.
Concomitant administration of PRINIVIL and hydochlorothiazide further reduced blood pressure
in black and non-black patients and any racial difference in blood pressure response was no
Pharmacokinetics and Metabolism
Following oral administration of PRINIVIL, peak serum concentrations of lisinopril occur within
about 7 hours, although there was a trend to a small delay in time taken to reach peak serum
concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a
prolonged terminal phase which does not contribute to drug accumulation. This terminal phase
probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not
appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based
on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with
large inter-subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption
is not influenced by the presence of food in the gastrointestinal tract. The absolute bioavailability
of lisinopril is reduced to about 16% in patients with stable NYHA Class II-IV congestive heart
failure and the volume of distribution appears to be slightly smaller than that in normal subjects.
The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in
Upon multiple dosing, lisinopril exhibits an effective half live of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through
the kidneys, but this decrease becomes clinically important only when the glomerular filtration
rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little
changed. With greater impairment, however, peak and trough, lisinopril levels increase, time to
peak concentration increases and time to attain steady state is prolonged. Older patients, on
average, have (approximately doubled) higher blood levels and area under the plasma
concentration time curve (AUC) than younger patients. (See DOSAGE AND
ADMINISTRATION.) Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of
lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains
radioactivity following administration of 14C lisinopril. By whole body autoradiography,
radioactivity was found in the placenta following administration of labeled drug to pregnant rats,
but none was found in the fetuses.
Pharmacodynamics and Clinical Effects
Hypertension: Administration of PRINIVIL to patients with hypertension results in a reduction of
supine and standing blood pressure to about the same extent with no compensatory tachycardia.
Symptomatic postural hypotension is usually not observed although it can occur and should be
anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given together
with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved
by six hours. Although an antihypertensive effect was observed 24 hours after dosing with
recommended single daily doses, the effect was more consistent and the mean effect was
considerably larger in some studies with doses of 20 mg or more than with lower doses.
However, at all doses studied, the mean antihypertensive effect was substantially smaller 24
hours after dosing than it was six hours after dosing.
In some patients achievement of optimal blood pressure reduction may require two to four weeks
The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt
withdrawal of PRINIVIL has not been associated with a rapid increase in blood pressure or a
significant increase in blood pressure compared to pretreatment levels.
Two dose response studies utilizing a once daily regimen were conducted in 438 mild to
moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after
dosing. An antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However,
in both studies blood pressure reduction occurred sooner and was greater in patients treated with
10, 20 or 80 mg of PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been
compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and
with atenolol 50-500 mg; and in patients with moderate to severe hypertension to metoprolol
100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic blood
pressure in a population that was 3/4 caucasian. PRINIVIL was approximately equivalent to
atenolol and metoprolol in effects on diastolic blood pressure and had somewhat greater effects
on systolic blood pressure.
PRINIVIL had similar effectiveness and adverse effects in younger and older (> 65 years)
patients. It was less effective in blacks than in causcasians.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac
output and in heart rate. In a study in nine hypertensive patients, following administration of
PRINIVIL, there was an increase in mean renal blood flow that was not significant. Data from
several small studies are inconsistent with respect to the effect of PRINIVIL on glomerular
filtration rate in hypertensive patients with normal renal function but, suggest that changes, if
any, are not large.
In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and
effective in controlling blood pressure (see PRECAUTIONS).
Heart Failure: During baseline-controlled clinical trials, in patients receiving digitalis and
diuretics, single doses of PRINIVIL resulted in decreases in pulmonary capillary wedge
pressure, systemic vascular resistance and blood pressure accompanied by an increase in
cardiac output and no change in heart rate.
In two placebo controlled, 12-week clinical studies, PRINIVIL as adjunctive therapy to digitalis
and diuretics improved the following signs and symptoms due to congestive heart failure:
edema, rales, paroxysmal nocturnal, dyspnea and jugular venous distention. In one of the
studies beneficial response was also noted for: orthopnea, presence of third heart sound and the
number of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in
this study. The effect of lisinopril on mortality in patients with heart failure has not been
Acute Myocardial Infarction: The Gruppo Italiano per lo Studio della Sopravvienza nell'Infarto
Miocardico (GISSI -3) study was a multicenter, controlled, randomized, unblinded clinical trial
conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It
was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates,
their combination, or no therapy on short-term (6 week mortality and on long-term death and
markedly impaired cardiac function. Patients presenting within 24 hours of the onset of
symptoms who were hemodynamically stable were randomized, in a 2 X 2 factorial design, to six
weeks of either
1) PRINIVIL alone (n = 4841),
2) nitrates alone (n = 4869),
3) PRINIVIL plus nitrates (n = 4841), or
4) open control (n = 4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-
blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure = 100 mmHg), severe
heart failure, cardiogenic shock and renal dysfunction (serum creatinine > 2 mg/dL and/or
proteinuria > 500 mg/24h). Doses of PRINIVIL were adjusted as necessary according to protocol.
(See DOSAGE AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated
continuation of treatment.
The primary outcomes of the trial were the overall mortality at six weeks, and a combined
endpoint at six months after the myocardial infarction, consisting of the number of patients who
died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage
defined as ejection fraction = 35% , or an akinetic-dyskinetic [A-D] score >/= 45%. Patients
receiving PRINIVIL (n = 9646) alone or with nitrates, had an 11 percent lower risk of death
(2p [two tailed] = 0.04) compared to patients receiving no PRINIVIL (n = 9672) (6.4 percent
versus 7.2 percent, respectively) at six weeks. Although patients randomized to receive
PRINIVIL for up to six weeks also fared numerically better on the combined end-point at 6
months, the open nature of the assessment of heart failure, substantial loss to follow-up
echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in
the group randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent versus
3.7 percent, respectively) incidence of persistent hypotension (systolic blood pressure < 90
mmHg for more than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-hospital
and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of
the baseline serum creatinine concentration). See ADVERSE REACTIONS, ACUTE
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INDICATIONS AND USAGE
PRINIVIL is indicated for the treatment of hypertension. It may be used alone as initial therapy
or concomitantly with other classes of antihypertensive agents.
PRINIVIL is indicated as adjunctive therapy in the management of heart failure in patients who
are not responding adequately to diuretics and digitalis.
Acute Myocardial Infarction
PRINIVIL is indicated for the treatment of hemodynamically stable patients within 24 hours of
acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the
standard recommended treatments such as thrombolytics, aspirin and beta blockers.
In using PRINIVIL, consideration should be given to the fact that another angiotensin converting
enzyme inhibitor, captopril, has caused agranulocytsis, particularly in patients with renal
impairment or collagen vascular disease and that available data are insufficient to show that
PRINIVIL does not have a similar risk. (See WARNINGS.)
In considering use of PRINIVIL, it should be noted that in controlled clinical trials ACE inhibitors
have an effect on blood pressure that is less in black patients than in non-blacks. In addition, it
should be noted that black patients receiving ACE inhibitors have been reported to have a higher
incidence of angioedema compared to non-blacks.
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PRINIVIL 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
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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 PRINIVIL) may be subject to a variety of adverse reactions, some of them
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been
reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL.
This may occur at any time during treatment. In such cases PRINIVIL should be promptly
discontinued and appropriate therapy and monitoring should be provided until complete and
sustained resolution of signs and symptoms has occurred. 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 laryngeal
edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause
airway obstruction, appropriate therapy, e.g. subcutaneous epinephrine solution 1:1000 (0.3 mL
to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided.
(See ADVERSE REACTIONS.)
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 INDICATIONS AND USAGE and
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 (a procedure dependent upon devices not
approved in the United States).
Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with
peak blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy
because of continuing symptomatic hypotension usually is not necessary when dosing
instructions are followed; caution should be observed when initiating therapy. (See DOSAGE
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include those with the following
conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg,
hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose,
renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to
eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase
salt intake cautiously before initiating therapy with PRINIVIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments. (See PRECAUTIONS, Drug Interactions,
and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus
3.7 percent) incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more
than 1 hour) when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute
myocardial infarction patients at risk of further serious hemodynamic deterioration after
treatmnent with a vasodilator (e.g. systolic blood pressure of 100 mmHg or lower) or cardiogenic
In patients at risk of excessive hypotension, therapy should be started under very close medical
supervision and such patients should be followed closely for the first two weeks of treatment and
whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to
patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial
infarction, in whom an excessive fall in blood pressure could result in a myocardial infarction or
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of PRINIVIL which usually can be given without difficulty
once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction
or discontinuation of PRINIVIL or concomitant diuretic may be necessary.
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. Available data from clinical trials of PRINIVIL are insufficient to show that PRINIVIL
does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases
of neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be
excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular
disease and renal disease should be considered.
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.
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, physicans should make every effort to discontinue the use of PRINIVIL 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
If oligohydramnios is observed, PRINIVIL should be discontinued unless it is considered
lifesaving 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.
Infant 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. Lisinopril,
which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis
with some clinical benefit, and theoretically may be removed by exchange transfusion, although
there is no experience with the latter procedure.
No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a
mg/kg basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in
rabbits) the maximum recommended human dose.
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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 PRINIVIL, 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
PRINIVIL and/or diuretic therapy. In such patients renal function should be monitored during the
first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular
disease have developed increases in blood urea nitrogen and serum creatinine, usually minor
and transient, especially when PRINIVIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or
discontinuation of the diuretic and/or PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a
higher (2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six
weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline
serum creatinine concentration). In acute myocardial infarction, treatment with PRINIVIL should
be initiated with caution in patients with evidence of renal dysfuntion, defined as serum
creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with
PRINIVIL (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-
treatment value) then the physician should consider withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should always
include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia (serum potasium greater than 5.7 mEq/L) occurred
in approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with heart
failure. In most cases these were isolated values which resolved despite continued therapy.
Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1 percent of
hypertensive patients, 0.6 percent of patients with heart failure and 0.1 percent of patients with
myocardial infarction. Risk factors for the development of hyperkalemia include renal
insufficiency, diabetes mellitus, and the concomitant use of potasssium-sparing diuretics,
potassium supplements and/or potassium-containing salt substitutes, which should be used
cautiously, if at all, with PRINIVIL. (See Drug Interactions.)
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
non productive 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.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, PRINIVIL may block angiotensin II formation secondary to compensatory
renin release. If hypotension occurs and is considered to be due to this mechanism, it can be
corrected by volume expansion.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment
with angiotensin-converting enzyme inhibitors, including lisinopril. Patients should be so advised
and told to report immediately any signs or symptoms suggesting angioedema (swelling of face,
extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug
until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially
during the first few days of therapy. If actual syncope occurs, the patients should be told to
discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive persipiration and dehydration may lead to an
excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume
depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should
be advised to consult with their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore
throat, fever) which may 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.
NOTE: As with many other drugs, certain advice to patients being treated with PRINIVIL is
warranted. This information is intended to aid in the safe and efffective use of this medication.
It is not a discloure of all possible adverse or intended effects.
Hypotension - Patients on Diuretic Therapy: Patients on diuretics, and especially those in whom
diuretic therapy was recently instituted, may occasionally experience an excessive reduction of
blood pressure after initiation of therapy with PRINIVIL. The possiblity of hypotensive effects
with PRINIVIL can be minimized by either discontinuing the diuretic or increasing the salt intake
prior to initiation of treatment with PRINIVIL. If it is necessary to continue the diuretic, initiate
therapy with PRINIVIL at a dose of 5 mg daily, and provide close medical supervision after the
initial dose until blood pressure has stabilized. (See WARNINGS and DOSAGE AND
AMINISTRATION.) When a diuretic is added to the therapy of a patient receiving PRINIVIL, an
additional antihypertensive effect is usually observed. Studies with ACE inhibitors in
combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is
given with a diuretic. (See DOSAGE AND ADMINISTRATION.)
Indomethacin: In a study in 36 patients with mild to moderate hypertension where the
antihypertensive effects of PRINIVIL alone were compared to PRINIVIL given concomitantly with
indomethacin, the use of indomethacin was associated with a reduced effect, although the
difference between the two regimens was not significant.
Other Agents: PRINIVIL has been used concomitantly with nitrates and/or digoxin without
evidence of clinically significant adverse interactions. This included post myocardial infarction
patients who were receiving intravenous or transdermal nitroglycerin. No clinically important
pharmacokinetic interactions occurred when PRINIVIL was used concomitantly with propranolol
or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of
Agents Increasing Serum Potassium: PRINIVIL attenuates potassium loss caused by thiazide-
type diuretics. Use of PRINIVIL with potassium-sparing diuretics (e.g. spironolactone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt substitiutes may
lead to significant increases in serum potassium. Therefore, if concomitant use of these agents
is indicated because of demonstrated hypokalemia, they should be used with caution and with
frequent monitoring of serum potassium. Potassium sparing agents should generally not be
used in patients with heart failure who are receiving PRINIVIL.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs
which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually
reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum
lithium levels be monitored frequently if PRINIVIL is administered concomitantly with lithium.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to
male and female rats at doses up to 90 mg/kg/day (about 56 times** the maximum
recommended daily human dose) or when lisinopril was administered for 92 weeks to (male and
female) mice at doses up to 135mg/kg/day (about 84 times** the maximum recommended daily
**Based on patient weight of 50 kg
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic
activation. It was also negative in a forward mutation assay using Chinese hamster lung cells.
Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte
assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro
test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
There were no advers effects on reporductive performance in male and female rats treated with
up to 300 mg/kg/day of lisinopril.
Pregnancey Caegories C (first trimester) and D second and third trimesters). See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not
known whether this drug is secreted in human milk. Because many drugs are secreted in human
milk, caution should be exercised when PRINIVIL is given to a nursing mother.
Safety and effectiveness in pediatric patients have not been established.
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PRINIVIL has been found to be generally well tolerated in controled clinical trials involving 1969
patients with hypertension or heart failure. For the most part, adverse experiences were mild
In clinical trials in patients with hypertension treated with PRINIVIL, discontinuation of therapy
due to clinical adverse experiences occurred in 5.7 percent of patients. The overall frequency of
adverse experiences could not be related to total daily dosage within the recommended
therapeutic dosage range.
For adverse experiences occurring in greater than one percent of patients with hypertension
treated with PRINIVIL or PRINIVIL plus hydrochlorothiazide in controlled clinical trials and more
frequently with PRINIVIL and/or PRINIVIL plus hydrochlorothiazide than placebo, comparative
incidence data are listed in the table below.
Percent of Patients in Controlled Studies
PRINIVIL Hydrochlorothiazide Placebo
(n=1349) (n=629) (n=207)
Incidence Incidence Incidence
(discontinuation) (discontin.) (discontin.)
Chest pain and back pain were also seen but were more common on placebo than PRINIVIL.
Body As A Whole
Fatigue 2.5(0.3) 4.0(0.5) 1.0(0.0)
Asthenia 1.3(0.5) 2.1(0.2) 1.0(0.0)
Orthostatic Effects 1.2(0.0) 3.5(0.3) 1.0(0.0)
Hypotension 1.2(0.5) 1.6(0.5) 0.5(0.5)
Diarrhea 2.7(0.2) 2.7(0.3) 2.4(0.0)
Nausea 2.0(0.4) 2.5(0.2) 2.4(0.0)
Vomiting 1.1(0.2) 1.4(0.1) 0.5(0.0)
Dyspepsia 0.9(0.0) 1.9(0.0) 0.0(0.0)
Muscle Cramps 0.5(0.0) 2.9(0.8) 0.5(0.0)
Headache 5.7(0.2) 4.5(0.5) 1.9(0.0)
Dizziness 5.4(0.4) 9.2(1.0) 1.9(0.0)
Paresthesia 0.8(0.1) 2.1(0.2) 0.0(0.0)
Decreased Libido 0.4(0.1) 1.3(0.1) 0.0(0.0)
Vertigo 0.2(0.1) 1.1(0.20) 0.0(0.0)
Cough 3.5(0.7) 4.6(0.8) 1.0(0.0)
Infection 2.1(0.1) 2.7(0.1) 0.0(0.0)
Common Cold 1.1(0.1) 1.3(0.1) 0.0(0.0)
Nasal Congestion 0.4(0.1) 1.3(0.1) 0.0(0.0)
Influenza 0.3(0.1) 1.1(0.1) 0.0(0.0)
Rash 1.3(0.4) 1.6(0.2) 0.5(0.5)
Impotence 1.0(0.4) 1.6(0.5) 0.0(0.0)
In patients with heart failure treated with PRINIVIL for up to four years, discontinuation of therapy
due to clinical adverse experiences occurred in 11.0 percent of patients. In controlled studies in
patients with heart failure, therapy was discontinued in 8.1 percent of patients treated with
PRINIVIL for up to 12 weeks, compared to 7.7 percent of patients treated with placebo for 12
The following table lists those adverse experiences which occurred in greater than one percent of
patients with heart failure treated with PRINIVIL or placebo for up to 12 weeks in controlled
clinical trials and more frequently on PRINIVIL than placebo.
Also observed at >1% with PRINIVIL but more frequent or as frequent on placebo than PRINIVIL
in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough and pruritis.
12 weeks 12 weeks
Body As A Whole
Chest Pain 3.4(0.2) 1.3(0.0)
Abdominal Pain 2.2(0.7) 1.9(0.0)
Hypotension 4.4(1.7) 0.6(0.6)
Diarrhea 3.7(0.5) 1.9(0.0)
Dizziness 11.8(1.2) 4.5(1.3)
Headache 4.4(0.2) 3.9(0.0)
Infection 1.5(0.0) 1.3(0.0)
Rash 1.7(0.5) 0.6(0.6)
Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia,
depression, chest should abnormalities and pulmonary edema were also seen in controlled
clinical trials, but were more common on placebo than PRINIVIL.
ACUTE MYOCARDIAL INFARCTION
In the GISSI - 3 trial, in patients treated with PRINIVIL for six weeks following acute myocardial
infarction, discontinuation of therapy occurred in 17.6 percent of patients.
Patients treated with PRINIVIL had a significantly higher incidence of hypotension and renal
dysfunction compared with patients not taking PRINIVIL.
In the GISSI - 3 trial, hypotension (9.7 percent), renal dysfunction (2.0 percent), cough (0.5
percent), post-infarction angina (0.3 percent) skin rash and generalized edema (0.01 percent),
and angioedema (0.01 percent) resulted in withdrawal of treatment. In elderly patients treated
with PRINIVIL, discontinuation due to renal dysfunction was 4.2 percent.
Other clinical adverse experiences occurring in 0.3 to 1.0 percent of patients with hypertension
or heart failure treated with PRINIVIL in controlled trials and rarer, serious, possibly drug-related
events reported in uncontrolled studies or marketing experience are listed below, and within each
category, are in order of decreasing severity:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possible
Related Reactions), syncope, orthostatic effects, chest, discomfort, pain, pelvic pain, flank pain,
edema, facial edema, virus infection, fever, chills, malaise.
Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly
secondary to excessive hypotension in high rish patients (see WARNINGS, Hypotension);
pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial
tachycardia, atrial fibrillation, bradycardia and premature ventricular contraction), palpitations,
transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased
blood pressure, peripheral edema, vasculitis.
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation,
flatulence, dry mouth.
Hematologic: Rare cases of bone marrow depression, neutropenia, and thrombocytopenia.
Endocrine: Diabetes mellitus.
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain.
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain,
knee pain, shoulder pain, arm pain, lumbago.
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral,
neuropathy (e.g. dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence,
hypersomnia, irritability, and nervousness.
Respiratory System: Malignant lung neoplasms, hemoptysis, pulmonary infiltrates,
bronchospasm, asthma, pleural effusion, pneumonia, bronchitis, wheezing, orthropnea painful
respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections,
pemphigus, erythema, flushing, diaphoresis. Other severe skin reactions (including toxic
epidermal necrolysis and Stevens-Johnson syndrome) have been reported rarely; causal
relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia.
Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal
dysfunction (see PRECAUSTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis,
dysuria, urinary tract infection, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis,
leukocytosis, eosinophilia, photosensitivity, rash, and other dermatological manifestations.
Angioedema: Angioedema has been reported in patients receiving PRINIVIL with an incidence
higher in black than in non-black patients. Angioedema associated with laryngeal edema may be
fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment
with PRINIVIL should be discontinued and appropriate therapy instituted immediately. (See
Hypotension: In hypertensive patients, hypotension occurred in 1.2 percent and syncope
occurred in 0.1 percent of patients. Hypotension or syncope was a cause for discontinuation of
therapy in 0.5 percent of hypertensive patients. In patients with heart failure, hypotension
occurred in 5.3 percent and syncope occurred in 1.8 percent of patients. These adverse
experiences were causes for discontinuation of therapy in 1.8 percent of these patients. In
patients treated with PRINIVIL for six weeks after acute myocardial infarction, hypotension
(systolic blood prssure 100 mmHg) resulted in discontinuation of therapy in 9.7 percent of
patients. (See WARNINGS.)
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and
Cough: See PRECAUTIONS, Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUSTIONS), hyponatremia.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,
reversible upon discontinuation of therapy, were observed in about 2.0 percent of patients with
essential hypertension treated with PRINIVIL alone. Increases were more common in patients
receiving concomitant diuretics and in patients with renal artery stenosis. (See PRECAUTIONS.)
Reversible minor increases in blood urea nitrogen and serum creatinine were observed in
approximately 11.6 percent of patients with heart failure on concomitant diuretic therapy.
Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases
of approximately 0.4 g percent and 1.3 vol percent, respectively) occurred frequently in patients
treated with PRINIVIL but were rarely of clinical importance in patients without some other cause
of anemia. In clinical trials, less than 0.1 percent of patients discontinued therapy due to
anemia. Hemolytic anemia has been reported; a causal relationship to lisinopril cannot be
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum billirubin have occurred
(see WARNINGS, Hepatic Failure).
In hypertensive patients, 2.0 percent discontinued therapy due to laboratory adverse
experiences, principally elevations in blood urea nitrogen (0.6 percent) serum creatinine (0.5
percent), and serum potassium (0.4 percent). In the heart failure trials, 3.4 percent of patients
discontinued therapy due to laboratory adverse experiences, 1.8 percent due to elevations in
blood urea nitrogen and/or creatinine and 0.6 percent due to elevations in serum potassium. In
the myocardial infarction trial, 2.0 percent of patients receiving PRINIVIL discontinued therapy
due to renal dysfunction (increasing creatinine concentration to over 3 mg/dL or a doubling or
more of the baseline serum creatinine concentration); less than 1.0 percent of patients
discontinued therapy due to other laboratory adverse experiences: 0.1 percent with
hyperkalemia and less than 0.1 percent with hepatic enzyme alterations.
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The oral LD50 of lisinopril is greater than 20g/kg in mice and rats. The most likely manifestation
of overdosage would be hypotension, for which the usual treatment would be intravenous
infusion of normal saline solution.
Lisinopril can be removed by hemodialysis.
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DOSAGE AND ADMINISTRATION
Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy, the
recommended intial dose is 10 mg once a day. Dosage should be adjusted according to blood
pressure response. The usual dosage range is 20 to 40 mg per day administered in a single
daily dose. The antihypertensive effect may disminsh toward the end of the dosing interval
regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can
be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory
control is being maintained for 24 hours. If it is not, an increase in dose should be considered.
Doses up to 80 mg have been used but do not appear to give a greater effect. If blood pressure
is not controlled with PRINIVIL alone, a low dose of a diuretic may be added.
Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the addition of
a diuretic, it may be possible to reduce the dose of PRINIVIL.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a
diuretic, symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL.
The diuretic should be discontinued, if possible, for two to three days before beginning therapy
with PRINIVIL to reduce the likelihood of hypotension. (See WARNINGS.) The dosage of
PRINIVIL should be adjusted according to blood pressure response. If the patient's blood
pressure is not controlled with PRINIVIL alone, diuretic therapy may be resumed as described
If the diuretic cannot be discontinued, an initial dose of 5 mg should be used 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.)
Concomitant administration of PRINIVIL with potassium supplements, potassium salt
substitiutes, or potassium-sparing diuretics may lead to increases of serum potassium (see
Dosage Adjustment in Renal Impairment: The usual dose of PRINIVIL (10 mg) is recommended
for patients with a creatinine clearance > 30 mL/min (serum creatinine of up to approximately 3
mg/dL). For patients with creatinine clearance > or = 10 mL/min < or =30 mL/min (serum creatinine
> or = 3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance < 10 mL/min
(usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may be titrated
upward until blood pressure is controlled or to a maximum of 40 mg daily.
Renal Status Creatinine- Initial Dose
Normal Renal > 30 mL/min 10 mg
Function to Mild
Moderate to Severe > /=10 < /=30 mL/min 5 mg
Dialysis Patients*** < 10 mL/min 2.5 mg*
*** See PRECAUTIONS, Hemodialysis Patients
*Dosage or dosing interval should be adjusted depending on the blood presuure response.
PRINIVIL is indicated as adjunctive therapy with diuretics and digitalis. The recommended
starting dose is 5 mg once a day.
When initiating treatment with lisinopril in patients with heart failure, the initial dose should be
administered under medical observation, especially in those patients with low blood pressure
(systolic blood pressure below 100 mmHG). The mean peak blood pressure lowering occurs six
to eight hours after dosing. Observation should continue until blood pressure is stable. The
concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which
may contribute to hypotension. (See WARNINGS and PRECAUTIONS, Drug Interactions.) The
appearance of hypotension after the initial dose of PRINIVIL does not preclude subsequent
careful dose titration with the drug, following effective management of the hypotension.
The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In
patients with heart failure who have hyponatremia (serum sodium <130mEq/L) or moderate to
severe renal impairment (creatinine clearance +30 mL/min or serum creatinine >3 mg/dL),
therapy with PRINIVIL should be initiated at a dose of 2.5 mg once a day uner close medical
supervision. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
Acute Myocardial Infarction
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute
myocardial infarction, the first dose of PRINIVIL is 5 mg given orally, followed by 5 mg after 24
hours, 10 mg after 48 hours and then 10 mg of PRINIVIL once daily. Dosing should continue for
six weeks. Patients should receive, as appropriate, the standard recommended treatments such
as thrombolytics, aspirin and beta-blockers. Patients with low systolic blood pressure (=120
mmHg) when treatment is started or during the first 3 days after the infarct should be given a
lower 2.5 mg oral dose of PRINIVIL (see WARNINGS). If hypotension occurs (systolic blood
pressure = 100 mm Hg) a daily maintenance dose of 5 mg may be given with temporary
reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure = 90
mmHg for more than 1 hour) PRINIVIL should be withdrawn. For patients who develop
symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.
Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute
myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with
evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL.
No evaluation of dosage adjustment in myocardial infarction patients with severe renal
impairment has been performed.
Use in Elderly
In general, blood pressure response and adverse experiences were similar in younger and older
patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that
maximum blood levels and area under the plasma concentration time curve (AUC) are doubled
in older patients, so that dosage adjustments should be made with particular caution.
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No. 3658 - Tablets PRINIVIL, 2.5 mg, are white, round flat-faced beveled edged compressed tablets, coded MSD on one side and 15 on the other. They are supplied as follows:
NDC 0006-0015-28 unit dose packages of 100
NDC 0006-0015-31 unit of use bottles of 30
NDC 0006-0015-58 unit of use bottles of 100.
No 3577 - Tablets PRINIVIL, 5mg, are white, shield shaped, scored, compressed tablets, with code MSD 19 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0019-28 unit dose packages of 100
NDC 0006-0019-58, unit of use bottles of 100
(6505-01-281-2771, 5 mg 100's)
NDC 0006-0019-94 unit of use bottles of 90
NDC 0006-0019-82 bottles of 1,000
NDC 0006-0019-86 bottles of 5,000
(6505-01-367-8874, 5 mg 5,000's).
No. 3578 - Tablets PRINIVIL, 10 mg, are light yellow, shield shaped compressed tablets, with code MSD 106 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0106-28 unit dose packages of 100
(6505-01-342-4861, 10 mg individually sealed 100's)
NDC 0006-0106-31 unit of use bottles of 30
NDC 0006-0106-58 unit of use bottles of 100
(6505-01-275-0061, 10 mg 100's)
NDC 0006-0106-94 unit of use bottles of 90
NDC 0006-0106-82 bottles of 1,000
NDC 0006-0106-86 bottles of 5,000
(6505-01-368-6604, 10 mg 5,000's)
NDC 0006-0106-87 bottles of 10,000
(6505-01-8064, 10 mg 10,000's).
No. 3579 - Tablets PRINIVIL, 20 mg, are peach, shield shaped, compressed tablets, with code MSD 207 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0207-28 unit dose packages of 100
NDC 0006-0207-31 unit of use bottles of 30
NDC 0006-0207-58 unit of use bottles of 100
(6505-01-282-6327, 20 mg 100's)
NDC 0006-0207-94 unit of use bottles of 90
NDC 0006-0207-82 bottles of 1,000
NDC 0006-0207-86 bottles of 5,000
NDC 0006-0207-87 bottles of 10,000
(6505-01-377-8066, 20 mg 10,000's).
No. 3580 - Tablets PRINIVIL 40 mg, are rose red, shield shaped, compressed tablets, with code MSD 237 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0237-58 unit of use bottles of 100.
Store at room temperature, 15-30 degrees Centigrade (59-86 degrees Fahrenheit), and protectfrom moisture.
Dispense in a tight container, if product package is subdivided.
West Point, PA 19486, USA
Issued November 1995
Printed in USA
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