LISINOPRIL/HCTZ- lisinopril/hctz tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LISINOPRIL (UNII: E7199S1YWR) (LISINOPRIL ANHYDROUS - UNII:7Q3P4BS2FD), HYDROCHLOROTHIAZIDE (UNII: 0J48LPH2TH) (HYDROCHLOROTHIAZIDE - UNII:0J48LPH2TH)
Available from:
Direct_Rx
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Lisinopril and Hydrochlorothiazide Tablets is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including lisinopril and hydrochlorothiazide. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a varie
Product summary:
Lisinopril and hydrochlorothiazide tablets, USP 10 mg/12.5 mg: Pink, round, unscored, flat-faced, beveled-edge tablets, debossed “WATSON” and “860” on the periphery of one side and plain on the other side are supplied in bottles of 100 and 500. Lisinopril and hydrochlorothiazide tablets, USP 20 mg/12.5 mg: Light blue, round, unscored, flat-faced, beveled-edge tablets, debossed “WATSON” and “861” on the periphery of one side and plain on the other side are supplied in bottles of 100 and 500. Lisinopril and hydrochlorothiazide tablets, USP 20 mg/25 mg: Pink, round, unscored, flat-faced, beveled-edge tablets, debossed “WATSON” and “862” on the periphery of one side and plain on the other side are supplied in bottles of 100 and 500. Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from excessive light and humidity. Dispense in a tight, light-resistant container according to USP/NF. Brands listed are trademarks of their respective owners. Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Revised: October 2017
Authorization status:
Abbreviated New Drug Application
Authorization number:
61919-523-30

LISINOPRIL/HCTZ- lisinopril/hctz tablet

Direct_Rx

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Lis inopril

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue Lisinopril and Hydrochlorothiazide Tablets as soon as

possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the

developing fetus. See WARNINGS, Fetal Toxicity.

Lisinopril and Hydrochlorothiazide Tablets, USP 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 C21H31N3O52H2O and its structural formula is:

[Structural Formula of Lisinopril]

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:

[Structural Formula of Hydrochlorothiazide]

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of

297.73, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Lisinopril and Hydrochlorothiazide Tablets, USP is available for oral use in three tablet combinations

of lisinopril with hydrochlorothiazide: Lisinopril and Hydrochlorothiazide Tablets, USP 10-12.5,

containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide USP and Lisinopril and

Hydrochlorothiazide Tablets, USP 20-12.5, containing 20 mg lisinopril and 12.5 mg

hydrochlorothiazide USP and Lisinopril and Hydrochlorothiazide Tablets 20-25, containing 20 mg

lisinopril and 25 mg hydrochlorothiazide USP. Inactive ingredients are colloidal silicon dioxide,

dibasic calcium phosphate, FD&C Blue #2 Aluminum Lake (20 mg/12.5 mg only), FD&C Red #40

Aluminum Lake (10 mg/12.5 mg, and 20 mg/25 mg), magnesium stearate, mannitol, and pregelatinized

starch.

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 renin-

angiotensin-aldosterone 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 Tablets 10-

12.5 combination worked equally well in Black and Caucasian patients. The Lisinopril and

Hydrochlorothiazide Tablets 20-12.5 and Lisinopril and Hydrochlorothiazide Tablets 20-25 (a

previously - marketed strength) 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 Tablets was sustained for at least 24 hours.

In a randomized, controlled comparison, the mean antihypertensive effects of Lisinopril and

Hydrochlorothiazide Tablets 20-12.5 and Lisinopril and Hydrochlorothiazide Tablets 20-25 were

similar, suggesting that many patients who respond adequately to the latter combination may be

controlled with Lisinopril and Hydrochlorothiazide Tablets 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

than0.5 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.

Lisinopril and Hydrochlorothiazide Tablets is indicated for the treatment of hypertension, to lower

blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events,

primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of

antihypertensive drugs from a wide variety of pharmacologic classes including lisinopril and

hydrochlorothiazide.

Control of high blood pressure should be part of comprehensive cardiovascular risk management,

including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,

exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood

pressure goals. For specific advice on goals and management, see published guidelines, such as those

of the National High Blood Pressure Education Program’s Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different

mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular

morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other

pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and

most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions

in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk

increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe

hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is

similar across populations with varying absolute risk, so the absolute benefit is greater in patients who

are at higher risk independent of their hypertension (for example, patients with diabetes or

hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a

lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and

many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart

failure, or diabetic kidney disease). These considerations may guide selection of therapy..

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.)

Lisinopril and Hydrochlorothiazide Tablets 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.

Lisinopril and Hydrochlorothiazide Tablets is contraindicated in combination with a neprilysin inhibitor

(e.g., sacubitril). Do not administer Lisinopril and Hydrochlorothiazide Tablets within 36 hours of

switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS).

Do not coadminister aliskiren with Lisinopril and Hydrochlorothiazide Tablets in patients with diabetes.

General

Lisinopril

Anaphylactoid and Possibly Related ReactionsPresumably because angiotensin-converting enzyme

inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin,

patients receiving ACE inhibitors (including Lisinopril and Hydrochlorothiazide Tablets) 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. ACE inhibitors have been associated with a

higher rate of angioedema in Black than in non-Black patients. In such cases Lisinopril and

Hydrochlorothiazide Tablets should be promptly discontinued and appropriate therapy and monitoring

should be provided until complete and sustained resolution of signs and symptoms has occurred. Even in

those instances where swelling of only the tongue is involved, without 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).

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin)

inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased

risk for angioedema (see PRECAUTIONS).

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: Sudden and potentially life-threatening

anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes and

treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and

aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by

antihistamines in these situations. In these patients, consideration should be given to using a different

type of dialysis membrane or a different class of antihypertensive agent. 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

Tablets. 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

be 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).

Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause

an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within

hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision

loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt

medical or surgical treatments may need to be considered if the intraocular pressure remains

uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of

sulfonamide or penicillin allergy.

Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of

pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting

oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential

neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When

pregnancy is detected, discontinue Lisinopril and Hydrochlorothiazide Tablets as soon as possible.

These adverse outcomes are usually associated with the use of these drugs in the second and third

trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to

antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin

system from other antihypertensive agents. Appropriate management of maternal hypertension during

pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative therapy to drugs affecting the renin-

angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform

serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed,

discontinue Lisinopril and Hydrochlorothiazide Tablets, unless it is considered lifesaving for the

mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians

should be aware, however, that oligohydramnios may not appear until after the fetus has sustained

irreversible injury. Closely observe infants with histories of in utero exposure to Lisinopril and

Hydrochlorothiazide Tablets for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS,

Pediatric Use).

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.

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.

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 Tablets should be used cautiously, if at all, with

these agents and with frequent monitoring of serum potassium. (See PRECAUTIONS, Drug

Interactions.)

Cough:

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive

cough has been reported with all ACE inhibitors, almost 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 renin 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

PRECAUTIONS, 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

Lisinopril and Hydrochlorothiazide Tablets during pregnancy. Discuss treatment options with women

planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon

as possible.

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: In

patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised

renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE

inhibitors, including lisinopril, may result in deterioration of renal function, including possible acute

renal failure. These effects are usually reversible. Monitor renal function periodically in patients

receiving lisinopril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs.

Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin

receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with

increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute

renal failure) compared to monotherapy.

The VA NEPHRON trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin to-

creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 ml/min), randomized

them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2

years. Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit

compared to monotherapy for the combined endpoint of decline in GFR, end state renal disease, or

death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with

the monotherapy group.

In general, avoid combined use of RAS inhibitors. Monitor blood pressure, renal function, and

electrolytes in patients on Lisinopril and Hydrochlorothiazide Tablets and other agents that affect the

RAS.

Do not coadminister aliskiren with Lisinopril and Hydrochlorothiazide Tablets in patients with diabetes.

Avoid use of aliskiren with PRINZIDE in patients with renal impairment (GFR <60 ml/min).

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 concomitant

ACE inhibitor therapy including Lisinopril and Hydrochlorothiazide Tablets.

mTOR (mammalian target of rapamycin) inhibitors: Patients receiving coadministration of ACE inhibitor

and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for

angioedema. (seeWARNINGS)

Neprilysin Inhibitors: Patients taking concomitant neprilysin inhibitors may be at increased risk for

angioedema. (see WARNINGS)

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 Tablets.

Non-steroidal Anti-inflammatory Drugs — In some patients, the administration of a non-steroidal anti-

inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-

sparing and thiazide diuretics. Therefore, when Lisinopril and Hydrochlorothiazide Tablets and non-

steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to

determine if the desired effect of Lisinopril and Hydrochlorothiazide Tablets 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 mcg/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.

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 Tablets, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to Lisinopril and Hydrochlorothiazide Tablets:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a 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.

Geriatric Use

Clinical studies of Lisinopril and Hydrochlorothiazide Tablets 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.)

Lisinopril and Hydrochlorothiazide Tablets have been evaluated for safety in 930 patients, including

100 patients treated for 50 weeks or more.

In clinical trials with Lisinopril and Hydrochlorothiazide Tablets 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.

Percent of Patients in Controlled Studies

Lisinopril and Hydrochlorothiazide

(n=930)

Incidence

(discontinuation) Placebo

(n=207)

Incidence

Dizziness 7.5 (0.8) 1.9

Headache 5.2 (0.3) 1.9

Cough 3.9 (0.6) 1.0

Fatigue 3.7 (0.4) 1.0

Orthostatic Effects 3.2 (0.1) 1.0

Diarrhea 2.5 (0.2) 2.4

Nausea 2.2 (0.1) 2.4

Upper Respiratory Infection 2.2 (0.0) 0.0

Muscle Cramps 2.0 (0.4) 0.5

Asthenia 1.8 (0.2) 1.0

Paresthesia 1.5 (0.1) 0.0

Hypotension 1.4 (0.3) 0.5

Vomiting 1.4 (0.1) 0.5

Dyspepsia 1.3 (0.0) 0.0

Rash 1.2 (0.1) 0.5

Impotence 1.2 (0.3) 0.0

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 PRINZIDE, 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 PRINZIDE

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 percent), orthostatic hypotension (0.5 percent), other orthostatic effects (3.2 percent). 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 Tablets. 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 Tablets 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 Tablets. 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 Tablets: 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, mood alterations (including depressive symptoms); hallucinations ;

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, psoriasis. 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, olfactory 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) (see WARNINGS, Hepatic Failure), pancreatitis,

sialadenitis, constipation; Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic

anemia, hemolyticanemia; 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.

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-

800-FDA-1088 or www.fda.gov/ for voluntary reporting adverse reactions.

No specific information is available on the treatment of overdosage with Lisinopril and

Hydrochlorothiazide Tablets. Treatment is symptomatic and supportive. Therapy with Lisinopril and

Hydrochlorothiazide Tablets 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 g/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 g/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.

Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10 mg to 80 mg,

while hydrochlorothiazide monotherapy is effective in doses of 12.5 mg to 50 mg per day. In clinical

trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10 mg to 80 mg

and hydrochlorothiazide doses of 6.25 mg to 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

dose-independent 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-

12.5 or Lisinopril and Hydrochlorothiazide Tablets 20-12.5. 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 10-12.5. 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 is

not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure).

Lisinopril and hydrochlorothiazide tablets, USP 10 mg/12.5 mg: Pink, round, unscored, flat-faced,

beveled-edge tablets, debossed “WATSON” and “860” on the periphery of one side and plain on the

other side are supplied in bottles of 100 and 500.

Lisinopril and hydrochlorothiazide tablets, USP 20 mg/12.5 mg: Light blue, round, unscored, flat-faced,

beveled-edge tablets, debossed “WATSON” and “861” on the periphery of one side and plain on the

other side are supplied in bottles of 100 and 500.

Lisinopril and hydrochlorothiazide tablets, USP 20 mg/25 mg: Pink, round, unscored, flat-faced,

beveled-edge tablets, debossed “WATSON” and “862” on the periphery of one side and plain on the

other side are supplied in bottles of 100 and 500.

Storage

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from excessive

light and humidity.

Dispense in a tight, light-resistant container according to USP/NF.

Brands listed are trademarks of their respective owners.

Manufactured by:

Watson Pharma Private Limited

Verna, Salcette Goa 403 722 INDIA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised: October 2017

LISINOPRIL/HCTZ

lisinopril/hctz tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 19 -523(NDC:0 59 1-0 8 6 1)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LISINO PRIL (UNII: E719 9 S1YWR) (LISINOPRIL ANHYDROUS - UNII:7Q3P4BS2FD)

LISINOPRIL

20 mg

HYDRO CHLO RO THIAZIDE (UNII: 0 J48 LPH2TH) (HYDROCHLOROTHIAZIDE -

UNII:0 J48 LPH2TH)

HYDROCHLOROTHIAZIDE 12.5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MANNITO L (UNII: 3OWL53L36 A)

STARCH, CO RN (UNII: O8 232NY3SJ)

DIBASIC CALCIUM PHO SPHATE DIHYDRATE (UNII: O7TSZ9 7GEP)

Product Characteristics

Color

blue ((Light blue))

S core

no sco re

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

WATSON;8 6 1

Contains

Packag ing

Dire ct_Rx

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -523-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 7/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 19 4

0 8 /0 7/20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(6 19 19 -523)

Revised: 8/2019

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