LISINOPRIL AND HYDROCHLOROTHIAZIDE TABLETS
-
lisinopril and
hydrochlorothiazide tablet
International Labs, Inc.
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LISINOPRIL AND HYDROCHLOROTHIAZIDE TABLETS USP - PACKAGE LABELSDESCRIPTION
DESCRIPTION
Lisinopril and hydrochlorothiazide tablets combines an angiotensin converting enzyme inhibitor, lisinopril,
and a diuretic, hydrochlorothiazide.
Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor. It
is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. 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,
sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its
empirical formula is C7H8ClN3O4S2 and its structural formula is:
which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Lisinopril and hydrochlorothiazide tablets are available for oral use in three tablet combinations of lisinopril
with hydrochlorothiazide: lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg, containing 10 mg
lisinopril and 12.5 mg hydrochlorothiazide, lisinopril and hydrochlorothiazide tablets 20 mg/12.5 mg,
containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide and lisinopril and hydrochlorothiazide tablets 20
mg/25 mg, containing 20 mg lisinopril and 25 mg hydrochlorothiazide.
Inactive ingredients are dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch and
starch. Lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg also contains FD and C Blue No. 2 Aluminum
Lake. Lisinopril and hydrochlorothiazide tablets 20 mg/12.5 mg also contains yellow iron oxide and lisinopril
and hydrochlorothiazide tablets 20 mg/25 mg also contain red iron oxide.
CLINICAL PHARMACOLOGY
Lisinopril-Hydrochlorothiazide
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone
secretion, and decreases serum potassium. Administration of lisinopril blocks the reninangiotensinaldosterone
axis and tends to reverse the potassium loss associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and
hydrochlorothiazide was approximately additive. The lisinopril and hydrochlorothiazide 10 mg/12.5 mg
combination worked equally well in Black and Caucasian patients. The lisinopril and hydrochlorothiazide
20 mg/12.5 mg and lisinopril and hydrochlorothiazide 20 mg/25 mg combinations appeared somewhat
less effective in Black patients, but relatively few Black patients were studied. In most patients, the
antihypertensive effect of lisinopril and hydrochlorothiazide was sustained for at least 24 hours.
In a randomized, controlled comparison, the mean antihypertensive effects of lisinopril and
hydrochlorothiazide 20 mg/12.5 mg and lisinopril and hydrochlorothiazide 20 mg/25 mg were similar,
suggesting that many patients who respond adequately to the latter combination may be controlled with
lisinopril and hydrochlorothiazide 20-12.5. (See DOSAGE AND ADMINISTRATION.)
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of
either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.
Lisinopril
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. 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. Removal of angiotensin
II negative feedback on renin secretion leads to increased plasma renin activity. In hypertensive patients
with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum
potassium was less than 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 lisinopril plus a thiazide diuretic showed essentially no change in serum potassium.
(See PRECAUTIONS.)
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 lisinopril remains to be elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression
of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low-renin
hypertension. Although lisinopril was antihypertensive in all races studied, Black hypertensive patients
(usually a low-renin hypertensive population) had a smaller average response to lisinopril monotherapy than
non-Black patients.
Pharmacokinetics and Metabolism
Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours. 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 intersubject
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.
Upon multiple dosing, lisinopril exhibits an effective half-life 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. However, 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
Administration of lisinopril 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.)
In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of
an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.
At recommended single daily doses, antihypertensive effects have been maintained for at least 24 hours
after dosing, although the effect at 24 hours was substantially smaller than the effect six hours after dosing.
The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt withdrawal of
lisinopril has not been associated with a rapid increase in blood pressure; nor with a significant overshoot
of pretreatment blood pressure.
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 lisinopril, 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 lisinopril 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 lisinopril has been shown to be well tolerated and effective in
controlling blood pressure (see PRECAUTIONS).
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal
blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of
electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately
equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.
After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been
followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At
least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the
placental but not the blood-brain barrier.
INDICATIONS AND USAGE
Lisinopril and hydrochlorothiazide tablets are indicated for the treatment of hypertension.
These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).
In using lisinopril and hydrochlorothiazide tablets, consideration should be given to the fact that an
angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen vascular disease, and that available data are insufficient to show that lisinopril
does not have a similar risk. (See WARNINGS.)
In considering use of lisinopril and hydrochlorothiazide tablets, it should be noted that Black patients receiving
ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-Blacks. (See
WARNINGS, Head and Neck Angioedema.)
CONTRAINDICATIONS
Lisinopril and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of
this product and in patients with a history of angioedema related to previous treatment with an angiotensin
converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the
hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to
other sulfonamide-derived drugs.
WARNINGS
General
Lisinopril
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 lisinopril and
hydrochlorothiazide) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including lisinopril.
This may occur at any time during treatment. In such cases lisinopril and hydrochlorothiazide should be
promptly discontinued and appropriate therapy and monitoring should be provided until complete and
sustained resolution of signs and symptoms has occurred. ACE inhibitors have been associated with a higher
rate of angioedema in Black than in non-Black patients. Even in those instances where swelling of only the
tongue is involved, where respiratory distress, patients may require prolonged observation since treatment
with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due
to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue,
glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.
Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction,
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 CONTRAINDICATIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.
These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was
no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed
by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after
stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients
on ACE inhibitors presenting with abdominal pain.
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 and Related Effects: Excessive hypotension was rarely seen in uncomplicated hypertensive
patients but is a possible consequence of lisinopril use in salt/volume-depleted persons, such as those
treated vigorously with diuretics or patients on dialysis. (See PRECAUTIONS, Drug Interactions and
ADVERSE REACTIONS.)
Syncope has been reported in 0.8 percent of patients receiving lisinopril and hydrochlorothiazide. In patients
with hypertension receiving lisinopril alone, the incidence of syncope was 0.1 percent. The overall incidence
of syncope may be reduced by proper titration of the individual components. (See PRECAUTIONS, Drug
Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive
hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and
rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients,
therapy should be started under very close medical supervision. Such patients should followed closely for
the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is increased. Similar
considerations apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in
blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an intravenous
infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which
usually can be given without difficulty once the blood pressure has increased after volume expansion.
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. Available data from clinical trials of
lisinopril are insufficient to show that lisinopril 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.
Hepatic Failure:
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis
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.
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may
precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease,
since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Lisinopril and
Hydrochlorothiazide).
Pregnancy
Lisinopril-Hydrochlorothiazide
Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril in combination
with 10 mg/kg/day of hydrochlorothiazide. This dose of lisinopril is 5 times (in mice) and 10 times (in rats)
the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis (mg/
m2); the dose of hydrochlorothiazide is 0.9 times (in mice) and 1.8 times (in rats) the MRHDD. Maternal
or fetotoxic effects were not seen in mice with the combination. In rats decreased maternal weight gain
and decreased fetal weight occurred down to 3/10 mg/kg/day (the lowest dose tested). Associated with
the decreased fetal weight was a delay in fetal ossification. The decreased fetal weight and delay in fetal
ossification were not seen in saline-supplemented animals given 90/10 mg/kg/day.
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, lisinopril and hydrochlorothiazide should be
discontinued as soon as possible. (See Lisinopril, Fetal/Neonatal Morbidity and Mortality, below.)
Lisinopril
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.
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor drug
during the first trimester of pregnancy appeared to have an increased risk of major congenital malformations
compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The
number of cases of birth defects is small and the findings of this study have not yet been repeated.
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 lisinopril and hydrochlorothiazide 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, lisinopril and hydrochlorothiazide 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.
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. 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 mice, rats, and rabbits. On a body surface
area basis, the doses used were up 55 times, 33 times, and 0.15 times, respectively, the MRHDD.
Hydrochlorothiazide
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their
respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided
no evidence of harm to the fetus. These doses are more than 150 times the MRHDD on a body surface area
basis. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal
jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.
PRECAUTIONS
General
Lisinopril
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with
caution to patients with obstruction in the outflow tract of the left ventricle.
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 lisinopril, 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 lisinopril 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 and serum creatinine, usually minor and transient, especially when lisinopril has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment.
Dosage reduction of lisinopril 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 1.4 percent of hypertensive patients treated with lisinopril plus hydrochlorothiazide. In most
cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause
of discontinuation of therapy. 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. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.
Lisinopril and hydrochlorothiazide should be used cautiously, if at all, with these agents and with frequent
monitoring of serum potassium. (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.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce
hypotension, lisinopril may block angiotensin II formation secondary to compensatory rennin release. If
hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed
at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte
determinations are particularly important when the patient is vomiting excessively or receiving parenteral
fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness
of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps,
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and
vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged
therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may
cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects
of digitalis (e.g., increased ventricular irritability). Because lisinopril reduces the production of aldosterone,
concomitant therapy with lisinopril attenuates the diuretic-induced potassium loss (see Drug Interactions,
Agents Increasing Serum Potassium).
Although any chloride deficit is generally mild and usually does not require specific treatment, except under
extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in
the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water
restriction, rather than administration of salt except in rare instances when the hyponatremia is life
threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.
Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during
thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic
therapy. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in
hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation
of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may
be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for
parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
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 perspiration 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 exposure to ACE inhibitors
during pregnancy. 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 lisinopril and hydrochlorothiazide
is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a
disclosure of all possible adverse or intended effects.
Drug Interactions
Lisinopril
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 lisinopril. The possibility of hypotensive effects with lisinopril can be minimized by
either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril. If it
is necessary to continue the diuretic, initiate therapy with lisinopril at a dose of 5 mg daily, and provide close
medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at
least an additional hour. (See WARNINGS and DOSAGE AND ADMINISTRATION.) When a diuretic is added
to the therapy of a patient receiving lisinopril, an additional antihypertensive effect is usually observed. (See
DOSAGE AND ADMINISTRATION.)
Non-steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 (COX-2) Inhibitors:
Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive effect
of ACE inhibitors, including lisinopril. This interaction should be given consideration in patients taking NSAIDs
or selective COX-2 inhibitors concomitantly with ACE inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volumedepleted,
including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory
drugs, including selective COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or
ACE inhibitors, may result in a further deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
These interactions should be considered in patients taking NSAIDS including selective COX-2 inhibitors
concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, monitor effects on
blood pressure and renal function when administering the combination, especially in the elderly.
Other Agents: Lisinopril has been used concomitantly with nitrates and/or digoxin without evidence of
clinically significant adverse interactions. No meaningful clinically important pharmacokinetic interactions
occurred when lisinopril was used concomitantly with propranolol, digoxin, or hydrochlorothiazide. The
presence of food in the stomach does not alter the bioavailability of lisinopril.
Agents Increasing Serum Potassium: Lisinopril attenuates potassium loss caused by thiazide-type
diuretics. Use of lisinopril with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene,
or amiloride), potassium supplements, or potassium-containing salt substitutes 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.
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 lisinopril is administered concomitantly with lithium.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been
reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concominant ACE
inhibitor therapy including lisinopril and hydrochlorothiazide.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics — potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) — dosage adjustment of the antidiabetic drug may be
required.
Other antihypertensive drugs — additive effect or potentiation.
Cholestyramine and colestipol resins — Absorption of hydrochlorothiazide is impaired in the
presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the
hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent,
respectively.
Corticosteroids, ACTH — intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine) — possible decreased response to pressor amines but not
sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) — possible increased responsiveness
to the muscle relaxant.
Lithium — should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium
and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such
preparations with lisinopril and hydrochlorothiazide.
Non-steroidal Anti-inflammatory Drugs — In some patients, the administration of a non-steroidal antiinflammatory
agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium
sparing and thiazide diuretics. Therefore, when lisinopril and hydrochlorothiazide and non-steroidal antiinflammatory
agents are used concomitantly, the patient should be observed closely to determine if the
desired effect of lisinopril and hydrochlorothiazide is obtained.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lisinopril-Hydrochlorothiazide
Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using
Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic activation or in a forward
mutation assay using Chinese hamster lung cells.
Lisinopril-hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution rat
hepatocyte assay. In addition, it 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.
Lisinopril
There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105 weeks to male
and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female mice at doses up to 135
mg/kg/day. These doses are 10 times and 7 times, respectively, the maximum recommended human daily
dose (MRHDD) when compared on a body surface area basis.
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 adverse effects on reproductive performance in male and female rats treated with up to 300
mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program
(NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses of up
to approximately 600 mg/kg/day (53 times the MRHDD when compared on a body surface area basis) or in
male and female rats at doses of up to approximately 100 mg/kg/day (18 times the MRHDD when compared
on a body surface area basis). The NTP, however, found equivocal evidence for hepatocarcinogenicity in
male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium
strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for
chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster
bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results
were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse
Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 μg/mL,
and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein
these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to
conception and throughout gestation. In mice and rats these doses are 9 times and 0.7 times, respectively,
the MRHDD when compared on a body surface area basis.
Pregnancy
Teratogenic Effect
Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Pregnancy,
Lisinopril, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether lisinopril is secreted in human milk. However, milk of lactating rats contains
radioactivity following administration of 14C lisinopril. In another study, lisinopril was present in rat milk at
levels similar to plasma levels in the dams. Thiazides do appear in human milk. Because of the potential for
serious reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a decision should be made
whether to discontinue nursing or to discontinue lisinopril and hydrochlorothiazide, taking into account the
importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of lisinopril and hydrochlorothiazide did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy. In a multiple-dose pharmacokinetic study in elderly versus young hypertensive patients
using the lisinopril/hydrochlorothiazide combination, area under the plasma concentration time curve (AUC)
increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient
should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Lisinopril and hydrochlorothiazide has been evaluated for safety in 930 patients, including 100 patients
treated for 50 weeks or more.
In clinical trials with lisinopril and hydrochlorothiazide no adverse experiences peculiar to this combination
drug have been observed. Adverse experiences that have occurred have been limited to those that have been
previously reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label extensions) with
any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5 percent), headache (5.2 percent),
cough (3.9 percent), fatigue (3.7 percent) and orthostatic effects (3.2 percent), all of which were more
common than in placebo-treated patients. Generally, adverse experiences were mild and transient in nature;
but see WARNINGS regarding angioedema and excessive hypotension or syncope. Discontinuation of
therapy due to adverse effects was required in 4.4 percent of patients, principally because of dizziness,
cough, fatigue and muscle cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus
hydrochlorothiazide in controlled clinical trials are shown below.
Clinical adverse experiences occurring in 0.3 to 1.0 percent of patients in controlled trials included:
Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection.
Cardiovascular: Palpitation, orthostatic hypotension. Digestive: Gastrointestinal cramps, dry mouth,
constipation, heartburn. Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia, foot
pain. Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence. Respiratory: Common
cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic
sinusitis, allergic rhinitis, pharyngeal discomfort. Skin: Flushing, pruritus, skin inflammation, diaphoresis.
Special Senses: Blurred vision, tinnitus, otalgia. Urogenital: Urinary tract infection.
Angioedema: Angioedema has been reported in patients receiving lisinopril and hydrochlorothiazide, 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
lisinopril and hydrochlorothiazide should be discontinued and appropriate therapy instituted immediately. In
rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including
lisinopril. (See WARNINGS.)
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension
(1.4), orthostatic hypotension (0.5), other orthostatic effects (3.2). In addition syncope occurred in 0.8
percent of patients. (See WARNINGS.)
Cough: See PRECAUTIONS, Cough.
Clinical Laboratory Test Findings
Serum Electrolytes: See PRECAUTIONS.
Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum creatinine
were observed in patients with essential hypertension treated with lisinopril and hydrochlorothiazide. More
marked increases have also been reported and were more likely to occur in patients with renal artery
stenosis. (See PRECAUTIONS.)
Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: See PRECAUTIONS.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.5 g percent and 1.5 vol percent, respectively) occurred frequently in hypertensive patients
treated with lisinopril and hydrochlorothiazide but were rarely of clinical importance unless another cause of
anemia coexisted. In clinical trials, 0.4 percent of patients discontinued therapy due to anemia.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see
WARNINGS, Hepatic Failure).
Other adverse reactions that have been reported with the individual components are listed below:
Lisinopril — In clinical trials adverse reactions which occurred with lisinopril were also seen with lisinopril
and hydrochlorothiazide. In addition, and since lisinopril has been marketed, the following adverse reactions
have been reported with lisinopril and should be considered potential adverse reactions for lisinopril
and hydrochlorothiazide: Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid
and Possibly Related Reactions), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills;
Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary
to excessive hypotension in high risk patients (see WARNINGS, Hypotension), pulmonary embolism and
infarction, worsening of heart failure, arrhythmias (including tachycardia, ventricular tachycardia, atrial
tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina pectoris,
transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema,
vasculitis; Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), gastritis, anorexia, flatulence, increased salivation; Endocrine: Diabetes mellitus,
syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: Rare cases of neutropenia,
thrombocytopenia, and bone marrow depression have been reported. Hemolytic anemia has been reported;
a causal relationship to lisinopril cannot be excluded; Metabolic: Gout, weight loss, dehydration, fluid
overload, weight gain; Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm
pain, lumbago; Nervous System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke,
nervousness, confusion, peripheral neuropathy (e.g., paresthesia, dysesthesia), spasm, hypersomnia,
irritability; Respiratory: Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates,
eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, wheezing, orthopnea,
painful respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities;
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus,
erythema. Other severe skin reactions (including toxic epidermal necrolysis, Stevens-Johnson syndrome
and cutaneous pseudolymphoma) have been reported rarely; causal relationship has not been established;
Special Senses: Visual loss, diplopia, photophobia, taste disturbances; Urogenital: Acute renal failure,
oliguria, anuria, uremia, progressive azotemia, renal dysfunction (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION), pyelonephritis, dysuria, 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.
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Pregnancy, Lisinopril, Fetal/Neonatal
Morbidity and Mortality.
Hydrochlorothiazide
Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation, cramping, jaundice (intrahepatic
cholestatic jaundice), pancreatitis, sialadenitis, constipation; Hematologic: Leukopenia, agranulocytosis,
thrombocytopenia, aplastic anemia, hemolytic anemia; Musculoskeletal: Muscle spasm; Nervous
System/ Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction, interstitial nephritis (see
WARNINGS); Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis
including toxic epidermal necrolysis, alopecia; Special Senses: Xanthopsia; Hypersensitivity: Purpura,
photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress
including pneumonitis and pulmonary edema, anaphylactic reactions.
OVERDOSAGE
No specific information is available on the treatment of overdosage with lisinopril and hydrochlorothiazide.
Treatment is symptomatic and supportive. Therapy with lisinopril and hydrochlorothiazide should be
discontinued and the patient observed closely. Suggested measures include induction of emesis and/
or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established
procedures.
Lisinopril
Following a single oral dose of 20 mg/kg, no lethality occurred in rats and death occurred in one of 20 mice
receiving the same dose. 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. (See WARNINGS, Anaphylactoid reactions during membrane
exposure.)
Hydrochlorothiazide
Oral administration of a single oral dose of 10 mg/kg to mice and rats was not lethal. The most common
signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia,
hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered,
hypokalemia may accentuate cardiac arrhythmias.
DOSAGE AND ADMINISTRATION
Lisinopril is an effective treatment of hypertension in once-daily doses of 10-80 mg, while hydrochlorothiazide
is effective in doses of 12.5-50 mg. In clinical trials of lisinopril/hydrochlorothiazide combination therapy
using lisinopril doses of 10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive
response rates generally increased with increasing dose of either component.
The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of dose; those
of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and doseindependent
phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with
any combination of lisinopril and hydrochlorothiazide will be associated with both sets of dose-independent
side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.
To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after
a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect
A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide
monotherapy may be switched to lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg or lisinopril and
hydrochlorothiazide tablets 20 mg/12.5 mg. Further increases of either or both components could depend
on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have
elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide,
but who experience significant potassium loss with this regimen, may achieve similar or greater blood
pressure control with less potassium loss if they are switched to lisinopril and hydrochlorothiazide tablets
10 mg/12.5 mg. Dosage higher than lisinopril 80 mg and hydrochlorothiazide 50 mg should not be used.
Replacement Therapy
The combination may be substituted for the titrated individual components.
Use in Renal Impairment
The usual regimens of therapy with lisinopril and hydrochlorothiazide tablets need not be adjusted as long
as the patient’s creatinine clearance is greater than 30 mL/min/1.73 m2 (serum creatinine approximately less than or equal to 3 mg/dL or
265 μmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so
lisinopril and hydrochlorothiazide tablets are not recommended (see WARNINGS, Anaphylactoid reactions
during membrane exposure).
HOW SUPPLIED
Lisinopril and Hydrochlorothiazide Tablets USP, 10 mg/12.5 mg are blue, hexagonal tablets, with “LL”
debossed on one side and “B01” on other side.
They are supplied as follows:
NDC 54458-993-09 – in Shellpaks® of 30 tablets
Lisinopril and Hydrochlorothiazide Tablets USP, 20 mg/12.5 mg are yellow, round tablets, with “LL” debossed
on one side and “B02” on other side.
They are supplied as follows:
NDC 54458-992-10 – in Shellpaks® of 30 tablets
Lisinopril and Hydrochlorothiazide Tablets USP, 20 mg/25 mg are peach, round tablets, with “LL” debossed
on one side and “B03” on other side.
They are supplied as follows:
NDC 54458-991-10 – in Shellpaks® of 30 tablets
Storage
Store at 20°-25°C (68°-77°F). [See USP Controlled Room Temperature]. Protect from excessive light and
humidity.
Manufactured by:
Lupin Limited
Mumbai 400 098
INDIA
Packaged by:
International Labs, Inc.
St. Petersburg, FL 33710
Distributed by:
Wal-Mart
Bentonville, AR 72716
LISINOPRIL AND HYDROCHLOROTHIAZIDE TABLETS USP 10 12.5 mg
LB0010 - Lisinopril HCTZ Tablets USP 10 12.5 mg
LISINOPRIL AND HYDROCHLOROTHIAZIDE TABLETS USP 20 12.5 mg
LB0011 Lisinopril HCTZ Tablets USP 20 12.5 mg
LISINOPRIL AND HYDROCHLOROTHIAZIDE TABLETS USP 20 25 mg
LB0012 Lisinopril HCTZ Tablets USP 20 25 mg
| LISINOPRIL AND HYDROCHLOROTHIAZIDE
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| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA077912 | 12/15/2007 | |
| LISINOPRIL AND HYDROCHLOROTHIAZIDE
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lisinopril and hydrochlorothiazide tablet |
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| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA077912 | 12/15/2007 | |
| LISINOPRIL AND HYDROCHLOROTHIAZIDE
TABLETS
lisinopril and hydrochlorothiazide tablet |
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA077912 | 12/15/2007 | |
| Labeler - International Labs, Inc. (023569924) |
| Registrant - International Labs, Inc. (023569924) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| International Labs, Inc. | 023569924 | manufacture, relabel, repack | |