DESCRIPTION

Lisinopril is an oral long-acting angiotensin converting enzyme inhibitor. Lisinopril, a synthetic peptide

derivative, 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 441.53. It is soluble in

water and sparingly soluble in methanol and practically insoluble in ethanol.

Lisinopril tablet is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg tablets for oral

administration.

Inactive Ingredients:

2.5 mg, 5 mg, 10 mg tablets – dibasic calcium phosphate dihydrate, povidone, pregelatinized starch,

mannitol, colloidal silicon dioxide, corn starch, magnesium stearate.

20 mg, 30 mg, 40 mg tablets - dibasic calcium phosphate dihydrate, povidone, pregelatinized starch,

mannitol, colloidal silicon dioxide, corn starch, magnesium stearate, ferric oxide yellow (for 20 mg),

ferric oxide red (for 30 mg) and ferric oxide brown (for 40 mg).

CLINICAL PHARMACOLOGY

INDICATIONS AND USAGE

Hypertension

Lisinopril tablet is indicated for the treatment of hypertension. It may be used alone as initial therapy or

concomitantly with other classes of antihypertensive agents.

Heart Failure

Lisinopril tablet is indicated as adjunctive therapy in the management of heart failure in patients who

are not responding adequately to diuretics and digitalis.

Acute Myocardial Infarction

Lisinopril tablet is indicated for the treatment of hemodynamically stable patients within 24 hours of

acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard

recommended treatments such as thrombolytics, aspirin and beta blockers.

In using Lisinopril tablet, consideration should be given to the fact that another angiotensin-converting

enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment

or collagen vascular disease, and that available data are insufficient to show that Lisinopril tablet does

not have a similar risk. (See WARNINGS.)

In considering the use of Lisinopril tablet, it should be noted that in controlled clinical trials ACE

inhibitors have an effect on blood pressure that is less in Black patients than in non-Blacks. In addition,

ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black

patients (see WARNINGS, Anaphylactoid and Possibly Related Reactions).

CONTRAINDICATIONS

Lisinopril tablet is contraindicated in patients who are hypersensitive to this product and in patients with

a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor

and in patients with hereditary or idiopathic angioedema.

WARNINGS

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 tablet) 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

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx

has been reported in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril

tablet. 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. Lisinopril tablet 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, appropriate therapy, e.g., subcutaneous epinephrine solution

1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway should be

promptly provided. (See ADVERSE REACTIONS.)

Intestinal angioedema: Intestinal angioedema has been reported in patients treated with ACE

to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution

1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway should be

promptly provided. (See ADVERSE REACTIONS.)

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.

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).

Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment

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

Sudden and potentially life threatening

anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g.,

AN69®*) 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

Excessive hypotension is rare in patients with uncomplicated hypertension treated with Lisinopril tablet

alone.

Patients with heart failure given Lisinopril tablet commonly have some reduction in blood pressure, with

peak blood pressure reduction occurring 6 to 8 hours post dose. Evidence from the two-dose ATLAS

trial suggested that incidence of hypotension may increase with dose of lisinopril in heart failure

patients. Discontinuation of therapy because of continuing symptomatic hypotension usually is not

necessary when dosing instructions are followed; caution should be observed when initiating therapy.

(See DOSAGE AND ADMINISTRATION.)

Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive

azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or

characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high dose

diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume

and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients

with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy

with Lisinopril tablet in patients at risk for excessive hypotension who are able to tolerate such

adjustments. (See PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS.)

Patients with acute myocardial infarction in the GISSI-3 trial had a higher (9.0% versus 3.7%)

incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) when

treated with Lisinopril tablet. Treatment with Lisinopril tablet must not be initiated in acute myocardial

infarction patients at risk of further serious hemodynamic deterioration after treatment with a

vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.

In patients at risk of excessive hypotension, therapy should be started under very close medical

supervision and such patients should be followed closely for the first two weeks of treatment and

whenever the dose of Lisinopril tablet and/or diuretic is increased. Similar considerations may apply to

patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction,

in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular

accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary,

receive an intravenous infusion of normal saline. A transient hypotensive response is not a

contraindication to further doses of Lisinopril tablet which usually can be given without difficulty once

the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or

discontinuation of Lisinopril tablet or concomitant diuretic may be necessary.

Leukopenia/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 tablet are insufficient to show that Lisinopril tablet does not cause agranulocytosis at

similar rates. Marketing experience has revealed rare cases of leukopenia/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.

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 their 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 tablet 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 tablet should be discontinued unless it is considered

lifesaving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical

profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians

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

irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for

hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support

of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of

reversing hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the

placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit,

and theoretically may be removed by exchange transfusion, although there is no experience with the

latter procedure.

No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg

basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the

maximum recommended human dose.

WARNINGS

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 tablet) 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

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx

has been reported in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril

tablet. 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. Lisinopril tablet 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, appropriate therapy, e.g., subcutaneous epinephrine solution

1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway should be

promptly provided. (See ADVERSE REACTIONS.)

Intestinal angioedema: Intestinal angioedema has been reported in patients treated with ACE

to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution

1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway should be

promptly provided. (See ADVERSE REACTIONS.)

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.

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).

Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment

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

Sudden and potentially life threatening

anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g.,

AN69®*) 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

Excessive hypotension is rare in patients with uncomplicated hypertension treated with Lisinopril tablet

alone.

Patients with heart failure given Lisinopril tablet commonly have some reduction in blood pressure, with

peak blood pressure reduction occurring 6 to 8 hours post dose. Evidence from the two-dose ATLAS

trial suggested that incidence of hypotension may increase with dose of lisinopril in heart failure

patients. Discontinuation of therapy because of continuing symptomatic hypotension usually is not

necessary when dosing instructions are followed; caution should be observed when initiating therapy.

(See DOSAGE AND ADMINISTRATION.)

Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive

azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or

characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high dose

diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume

and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients

with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy

with Lisinopril tablet in patients at risk for excessive hypotension who are able to tolerate such

adjustments. (See PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS.)

Patients with acute myocardial infarction in the GISSI-3 trial had a higher (9.0% versus 3.7%)

incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) when

treated with Lisinopril tablet. Treatment with Lisinopril tablet must not be initiated in acute myocardial

infarction patients at risk of further serious hemodynamic deterioration after treatment with a

vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.

In patients at risk of excessive hypotension, therapy should be started under very close medical

supervision and such patients should be followed closely for the first two weeks of treatment and

whenever the dose of Lisinopril tablet and/or diuretic is increased. Similar considerations may apply to

patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction,

in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular

accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary,

receive an intravenous infusion of normal saline. A transient hypotensive response is not a

contraindication to further doses of Lisinopril tablet which usually can be given without difficulty once

the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or

discontinuation of Lisinopril tablet or concomitant diuretic may be necessary.

Leukopenia/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 tablet are insufficient to show that Lisinopril tablet does not cause agranulocytosis at

similar rates. Marketing experience has revealed rare cases of leukopenia/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.

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 their 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 tablet 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 tablet should be discontinued unless it is considered

lifesaving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical

profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians

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

irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for

hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support

of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of

reversing hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the

placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit,

and theoretically may be removed by exchange transfusion, although there is no experience with the

latter procedure.

No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg

basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the

maximum recommended human dose.

PRECAUTIONS

ADVERSE REACTIONS

ADVERSE REACTIONS

Lisinopril tablet has been found to be generally well tolerated in controlled clinical trials involving 1969

patients with hypertension or heart failure. For the most part, adverse experiences were mild and

transient.

Hypertension

In clinical trials in patients with hypertension treated with Lisinopril tablet, discontinuation of therapy

due to clinical adverse experiences occurred in 5.7% of patients. The overall frequency of adverse

experiences could not be related to total daily dosage within the recommended therapeutic dosage

range.

For adverse experiences occurring in greater than 1% of patients with hypertension treated with

Lisinopril tablet or Lisinopril tablet plus hydrochlorothiazide in controlled clinical trials, and more

frequently with Lisinopril tablet and/or Lisinopril tablet plus hydrochlorothiazide than placebo,

comparative incidence data are listed in the table below:

PERCENT OF PATIENTS IN CONTROLLED STUDIES

Lisinopril tablet      (n=1349)   Incidence (discontinuation)

Lisinopril tablet/Hydrochlorothiazide  (n=629) Incidence (discontinuation)

PLACEBO

(n=207) Incidence (discontinuation)

Body as a Whole

Fatigue 2.5 (0.3) 4.0 (0.5) 1.0 (0.0)

Asthenia 1.3 (0.5) 2.1 (0.2) 1.0 (0.0)

Orthostatic Effects 1.2 (0.0) 3.5 (0.2) 1.0 (0.0)

Cardiovascular

Hypotension 1.2 (0.5) 1.6 (0.5) 0.5 (0.5)

Digestive

Diarrhea 2.7 (0.2) 2.7 (0.3) 2.4 (0.0)

Nausea 2.0 (0.4) 2.5 (0.2) 2.4 (0.0)

Vomiting 1.1 (0.2) 1.4 (0.1) 0.5 (0.0)

Dyspepsia 0.9 (0.0) 1.9 (0.0) 0.0 (0.0)

Musculoskeletal

Muscle Cramps 0.5 (0.0) 2.9 (0.8) 0.5 (0.0)

Nervous/Psychiatric

Headache 5.7 (0.2) 4.5 (0.5) 1.9 (0.0)

Dizziness 5.4 (0.4) 9.2 (1.0) 1.9 (0.0)

Paresthesia 0.8 (0.1) 2.1 (0.2) 0.0 (0.0)

Decreased Libido 0.4 (0.1) 1.3 (0.1) 0.0 (0.0)

Vertigo 0.2 (0.1) 1.1 (0.2) 0.0 (0.0)

Respiratory

Cough 3.5 (0.7) 4.6 (0.8) 1.0 (0.0)

Upper Respiratory Infection 2.1 (0.1) 2.7 (0.1) 0.0 (0.0)

Common Cold 1.1 (0.1) 1.3 (0.1) 0.0 (0.0)

Nasal Congestion 0.4 (0.1) 1.3 (0.1) 0.0 (0.0)

Influenza 0.3 (0.1) 1.1 (0.1) 0.0 (0.0)

Skin

Rash 1.3 (0.4) 1.6 (0.2) 0.5 (0.5)

Urogenital

Impotence 1.0 (0.4) 1.6 (0.5) 0.0 (0.0)

Chest pain and back pain were also seen, but were more common on placebo than Lisinopril tablet.

Heart Failure

In patients with heart failure treated with Lisinopril tablet for up to four years, discontinuation of therapy

due to clinical adverse experiences occurred in 11.0% of patients. In controlled studies in patients with

heart failure, therapy was discontinued in 8.1% of patients treated with Lisinopril tablet for 12 weeks,

compared to 7.7% of patients treated with placebo for 12 weeks.

The following table lists those adverse experiences which occurred in greater than 1% of patients with

heart failure treated with Lisinopril tablet or placebo for up to 12 weeks in controlled clinical trials, and

more frequently on Lisinopril tablet than placebo.

Controlled Trials

Lisinopril tablet  (n=407)  Incidence (discontinuation)

12 weeks Placebo (n=155) Incidence (discontinuation)

12 weeks

Body as a Whole

Chest Pain 3.4 (0.2) 1.3 (0.0)

Abdominal Pain 2.2 (0.7) 1.9 (0.0)

Cardiovascular

Hypotension 4.4 (1.7) 0.6 (0.6)

Digestive

Diarrhea 3.7 (0.5) 1.9 (0.0)

Nervous/Psychiatric

Dizziness 11.8 (1.2) 4.5 (1.3)

Headache 4.4 (0.2) 3.9 (0.0)

Respiratory

Upper Respiratory Infection 1.5 (0.0) 1.3 (0.0)

Skin

Rash 1.7 (0.5) 0.6 (0.6)

Also observed at >1% with Lisinopril tablet but more frequent or as frequent on placebo than Lisinopril

tablet in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough, and pruritus.

Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia,

depression, chest sound abnormalities, and pulmonary edema were also seen in controlled clinical

trials, but were more common on placebo than Lisinopril tablet.

In the two-dose ATLAS trial in heart failure patients, withdrawals due to adverse events were not

different between the low and high groups, either in total number of discontinuation (17-18%) or in rare

specific events (<1%). The following adverse events, mostly related to ACE inhibition, were reported

more commonly in the high dose group:

% of patients Events  High Dose (N=1568)

Low dose  (N=1596)

Dizziness 18.9 12.1

Hypotension 10.8 6.7

Creatinine increased 9.9 7.0

Hyperkalemia 6.4 3.5

NPN* increased 9.2 6.5

Syncope 7.0 5.1

*NPN = non-protein nitrogen

NPN = non-protein nitrogen

Acute Myocardial Infarction

In the GISSI-3 trial, in patients treated with Lisinopril tablet for six weeks following acute myocardial

infarction, discontinuation of therapy occurred in 17.6% of patients.

Patients treated with Lisinopril tablet had a significantly higher incidence of hypotension and renal

dysfunction compared with patients not taking Lisinopril tablet.

In the GISSI-3 trial, hypotension (9.7%), renal dysfunction (2.0%), cough (0.5%), post infarction angina

(0.3%), skin rash and generalized edema (0.01%), and angioedema (0.01%) resulted in withdrawal of

treatment. In elderly patients treated with Lisinopril tablet, discontinuation due to renal dysfunction was

4.2%.

Other clinical adverse experiences occurring in 0.3% to 1.0% of patients with hypertension or heart

failure treated with Lisinopril tablet in controlled clinical trials and rarer, serious, possibly drug-related

events reported in uncontrolled studies or marketing experience are listed below, and within each

category are in order of decreasing severity:

Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related

Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related

Reactions), syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial

edema, virus infection, fever, chills, malaise.

Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident possibly secondary

Cardiac arrest; myocardial infarction or cerebrovascular accident possibly secondary

to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism

and infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation,

bradycardia and premature ventricular contractions), palpitations, transient ischemic attacks,

paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema,

vasculitis.

Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic

Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic

Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry

mouth.

Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/ neutropenia

Rare cases of bone marrow depression, hemolytic anemia, leukopenia/ neutropenia

and thrombocytopenia.

Endocrine: Diabetes mellitus.

Diabetes mellitus.

Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain. Cases of hypoglycemia in

Weight loss, dehydration, fluid overload, gout, weight gain. Cases of hypoglycemia in

diabetic patients on oral antidiabetic agents or insulin have been reported in post-marketing experience

(See PRECAUTIONS, Drug Interactions).

Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee

Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee

pain, shoulder pain, arm pain, lumbago.

Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral neuropathy

Stroke, ataxia, memory impairment, tremor, peripheral neuropathy

(e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability and

nervousness.

Respiratory System: Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, bronchospasm,

Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, bronchospasm,

asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, bronchitis, wheezing, orthopnea,

painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.

Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus,

Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus,

erythema, flushing, diaphoresis, cutaneous pseudolymphoma. Other severe skin reactions have been

reported rarely, including toxic epidermal necrolysis and Stevens-Johnson syndrome; causal

relationship has not been established.

Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.

Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.

Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal

Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal

dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria,

urinary tract infection, breast pain.

Miscellaneous: A symptom complex has been reported which may include a positive ANA, an

A symptom complex has been reported which may include a positive ANA, an

elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and

leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in

combination with these symptoms.

Angioedema: Angioedema has been reported in patients receiving Lisinopril tablet (0.1%) with an

Angioedema has been reported in patients receiving Lisinopril tablet (0.1%) 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 tablet should be discontinued and appropriate therapy instituted immediately.

(See WARNINGS.)

In rare cases, intestinal angioedema has been reported in post marketing experience.

Hypotension: In hypertensive patients, hypotension occurred in 1.2% and syncope occurred in 0.1%

In hypertensive patients, hypotension occurred in 1.2% and syncope occurred in 0.1%

of patients with an incidence higher in Black than in non-Black patients. Hypotension or syncope was a

cause of discontinuation of therapy in 0.5% of hypertensive patients. In patients with heart failure,

hypotension occurred in 5.3% and syncope occurred in 1.8% of patients. These adverse experiences

were possibly dose-related (see above data from ATLAS Trial) and caused discontinuation of therapy

in 1.8% of these patients in the symptomatic trials. In patients treated with Lisinopril tablet for six

weeks after acute myocardial infarction, hypotension (systolic blood pressure ≤100 mmHg) resulted in

discontinuation of therapy in 9.7% of the patients. (See WARNINGS.)

Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Cough: See PRECAUTIONS – Cough

See PRECAUTIONS – Cough

Pediatric Patients: No relevant differences between the adverse experience profile for pediatric

No relevant differences between the adverse experience profile for pediatric

patients and that previously reported for adult patients were identified.

Clinical Laboratory Findings

Serum Electrolytes: Hyperkalemia (See PRECAUTIONS), hyponatremia.

Hyperkalemia (See PRECAUTIONS), hyponatremia.

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,

Minor increases in blood urea nitrogen and serum creatinine,

reversible upon discontinuation of therapy, were observed in about 2.0% of patients with essential

hypertension treated with Lisinopril tablet alone. Increases were more common in patients receiving

concomitant diuretics and in patients with renal artery stenosis. (See PRECAUTIONS.) Reversible

minor increases in blood urea nitrogen and serum creatinine were observed in approximately 11.6% of

patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved

when the dosage of the diuretic was decreased.

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of

Small decreases in hemoglobin and hematocrit (mean decreases of

approximately 0.4 g% and 1.3 vol%, respectively) occurred frequently in patients treated with Lisinopril

tablet but were rarely of clinical importance in patients without some other cause of anemia. In clinical

trials, less than 0.1% of patients discontinued therapy due to anemia. Hemolytic anemia has been

reported; a causal relationship to lisinopril cannot be excluded.

Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred. (See

Rarely, elevations of liver enzymes and/or serum bilirubin have occurred. (See

WARNINGS, Hepatic Failure.)

In hypertensive patients, 2.0% discontinued therapy due to laboratory adverse experiences, principally

elevations in blood urea nitrogen (0.6%), serum creatinine (0.5%) and serum potassium (0.4%).

In the heart failure trials, 3.4% of patients discontinued therapy due to laboratory adverse experiences;

1.8% due to elevations in blood urea nitrogen and/or creatinine and 0.6% due to elevations in serum

potassium.

In the myocardial infarction trial, 2.0% of patients receiving Lisinopril tablet discontinued therapy due to

renal dysfunction (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the

baseline serum creatinine concentration); less than 1.0% of patients discontinued therapy due to other

laboratory adverse experiences: 0.1% with hyperkalemia and less than 0.1% with hepatic enzyme

alterations.

OVERDOSAGE

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.)

DOSAGE AND ADMINISTRATION

Hypertension

Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy, the

In patients with uncomplicated essential hypertension not on diuretic therapy, the

recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood

pressure response. The usual dosage range is 20 to 40 mg per day administered in a single daily

dose. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the

administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by

measuring blood pressure just prior to dosing to determine whether satisfactory control is being

maintained for 24 hours. If it is not, an increase in dose should be considered. Doses up to 80 mg have

been used but do not appear to give greater effect. If blood pressure is not controlled with Lisinopril

tablet alone, a low dose of a diuretic may be added. Hydrochlorothiazide, 12.5 mg has been shown to

provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of

Lisinopril tablet.

Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic,

: In hypertensive patients who are currently being treated with a diuretic,

symptomatic hypotension may occur occasionally following the initial dose of Lisinopril tablet. The

diuretic should be discontinued, if possible, for two to three days before beginning therapy with

Lisinopril tablet to reduce the likelihood of hypotension. (See WARNINGS.) The dosage of Lisinopril

tablet should be adjusted according to blood pressure response. If the patient"s blood pressure is not

controlled with Lisinopril tablet alone, diuretic therapy may be resumed as described above.

If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical supervision

for at least two hours and until blood pressure has stabilized for at least an additional hour. (See

WARNINGS and PRECAUTIONS, Drug Interactions.)

Concomitant administration of Lisinopril tablet with potassium supplements, potassium salt substitutes,

or potassium-sparing diuretics may lead to increases of serum potassium. (See PRECAUTIONS.)

Dosage Adjustment in Renal Impairment: The usual dose of Lisinopril tablet (10 mg) is

The usual dose of Lisinopril tablet (10 mg) is

recommended for patients with creatinine clearance >30 mL/min (serum creatinine of up to

approximately 3 mg/dL). For patients with creatinine clearance ≥10 mL/min ≤30 mL/min (serum

creatinine ≥3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance <10

mL/min (usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may be titrated

upward until blood pressure is controlled or to a maximum of 40 mg daily.

Renal Status Creatinine Clearance mL/min Initial Dose mg/day Normal Renal Function to

Mild Impairment >30 10

Moderate to Severe Impairment ≥10 ≤30 5

Dialysis Patients* <10 2.5**

* See WARNINGS, Anaphylactoid Reactions During Membrane Exposure.

* See WARNINGS, Anaphylactoid Reactions During Membrane Exposure.

**Dosage or dosing interval should be adjusted depending on the blood pressure response.

Dosage or dosing interval should be adjusted depending on the blood pressure response.

Heart Failure

Lisinopril tablet is indicated as adjunctive therapy with diuretics and (usually) digitalis. The

recommended starting dose is 5 mg once a day. When initiating treatment with lisinopril in patients with

heart failure, the initial dose should be administered under medical observation, especially in those

patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood

pressure lowering occurs six to eight hours after dosing. Observation should continue until blood

pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize

hypovolemia which may contribute to hypotension. (See WARNINGS and PRECAUTIONS, Drug

Interactions.) The appearance of hypotension after the initial dose of Lisinopril tablet does not preclude

subsequent careful dose titration with the drug, following effective management of the hypotension.

The usual effective dosage range is 5 to 40 mg per day administered as a single daily dose. The dose

of Lisinopril tablet can be increased by increments of no greater than 10 mg, at intervals of no less

than 2 weeks to the highest tolerated dose, up to a maximum of 40 mg daily. Dose adjustment should

be based on the clinical response of individual patients.

Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In

In

patients with heart failure who have hyponatremia (serum sodium <130 mEq/L) or moderate to severe

renal impairment (creatinine clearance ≤30 mL/min or serum creatinine >3 mg/dL), therapy with

Lisinopril tablet should be initiated at a dose of 2.5 mg once a day under close medical supervision.

(See WARNINGS and PRECAUTIONS, Drug Interactions.)

Acute Myocardial Infarction

In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial

infarction, the first dose of Lisinopril tablet is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg

after 48 hours and then 10 mg of Lisinopril tablet once daily. Dosing should continue for six weeks.

Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics,

aspirin, and beta-blockers.

Patients with a low systolic blood pressure (≤120 mmHg) when treatment is started or during the first 3

days after the infarct should be given a lower 2.5 mg oral dose of Lisinopril tablet (see WARNINGS). If

hypotension occurs (systolic blood pressure ≤100 mmHg) a daily maintenance dose of 5 mg may be

given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood

pressure <90 mmHg for more than 1 hour) Lisinopril tablet should be withdrawn. For patients who

develop symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.

Dosage Adjustment in Patients With Myocardial Infarction with Renal Impairment: In acute

In acute

myocardial infarction, treatment with Lisinopril tablet should be initiated with caution in patients with

evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No

evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has

been performed

Use in Elderly

In general, the clinical response was similar in younger and older patients given similar doses of

Lisinopril tablet. Pharmacokinetic studies, however indicate that maximum blood levels and area under

the plasma concentration time curve (AUC) are doubled in older patients, so that dosage adjustments

should be made with particular caution.

Pediatric Hypertensive Patients ≥6 Years of age

≥6 Years of age

The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be

adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have

not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and

Metabolism and Pharmacodynamics and Clinical Effects.)

Lisinopril tablet is not recommend in pediatric patients <6 years or in pediatric patients with glomerular

filtration rate <30 mL/min/1.73 min2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics and

Metabolism and Pharmacodynamics and Clinical Effects and PRECAUTIONS).

Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension): Add 10 mL of Purified Water

Add 10 mL of Purified Water

USP to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of Lisinopril tablet and

shake for at least one minute. Add 30 mL of Bicitra®† diluent and 160 mL of Ora Sweet SF™†† to the

concentrate in the PET bottle and gently shake for several seconds to disperse the ingredients. The

suspension should be stored at or below 250C (770F) and can be stored for up to four weeks. Shake

the suspension before each use.

† Registered trademark of Alza Corporation

Registered trademark of Alza Corporation

†† Trademark of Paddock Laboratories, Inc.

Trademark of Paddock Laboratories, Inc.

HOW SUPPLIED

2.5 mg Tablets, white to off-white, round biconvex uncoated tablets debossed with “W” on one side

white to off-white, round biconvex uncoated tablets debossed with “W” on one side

and other side plain.

(NDC 0615-7639-39) Blistercards of 30 tablets

(NDC 0615-7639-31) Blistercards of 31 tablets

5 mg Tablets, white to off-white, round biconvex uncoated tablets debossed with “ ” on one side and

white to off-white, round biconvex uncoated tablets debossed with “ ” on one side and

breakline on other side.

(NDC 0615-7540-39) Blistercards of 30 tablets

(NDC 0615-7540-31) Blistercards of 31 tablets

(NDC 0615-7540-05) Blistercards of 15 tablets

10 mg Tablets, white to off-white, round biconvex uncoated tablets debossed with “ ” on one side

white to off-white, round biconvex uncoated tablets debossed with “ ” on one side

and other side plain.

(NDC 0615-7541-39) Blistercards of 30 tablets

(NDC 0615-7541-31) Blistercards of 31 tablets

(NDC 0615-7541-05) Blistercards of 15 tablets

20 mg Tablets, mottled light yellow, round biconvex uncoated tablets debossed with

mottled light yellow, round biconvex uncoated tablets debossed with

“ ” on one side and other side plain.

(NDC 0615-7642-39) Blistercards of 30 tablets

(NDC 0615-7542-31) Blistercards of 31 tablets

(NDC 0615-7542-05) Blistercards of 15 tablets

30 mg Tablets, mottled light red, round biconvex uncoated tablets debossed with “ ” on one side

mottled light red, round biconvex uncoated tablets debossed with “ ” on one side

and other side plain.

(NDC 0615-7643-39) Bottles of 30 tablets

40 mg Tablets, mottled light brown, round biconvex uncoated tablets debossed with

mottled light brown, round biconvex uncoated tablets debossed with

“ ” on one side and other side plain.

(NDC 0615-7644-39) Blistercards of 30 tablets

(NDC 0615-7644-31) Blistercards of 31 tablets

(NDC 0615-7644-05) Blistercards of 15 tablets

REFERENCES

Storage

Store at controlled room temperature, 20-250C (68-770F) [see USP]. Protect from moisture, freezing

and excessive heat. Dispense in a tight container.

*AN69 is a registered trademark of Hospal Ltd.

AN69 is a registered trademark of Hospal Ltd.

Manufactured by:

Wockhardt Limited

Mumbai, India.

Distributed by:

Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054

USA.

Iss.080409

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 Lisinopril Tabs, USP

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