Zestril (Lisinopril): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Zestril

Lisinopril is an oral long-acting angiotensin converting enzyme (ACE) inhibitor. Lisinopril, a synthetic peptide derivative, is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-Lproline dihydrate. Its empirical formula is C₂₁H₃₁N₃O₅2H₂O 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.

Zestril 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 tablets - calcium phosphate, magnesium stearate, mannitol, starch.

5, 10, 20 and 30 mg tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch.

40 mg tablets - calcium phosphate, magnesium stearate, mannitol, starch, yellow ferric oxide.

Uses for Zestril

Hypertension

Zestril is indicated for the treatment of hypertension inadult patients and pediatric patients 6 years of age and older to lower bloodpressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascularevents, primarily strokes and myocardial infarctions. These benefits have beenseen in controlled trials of antihypertensive drugs from a wide variety ofpharmacologic classes.

Control of high blood pressure should be part ofcomprehensive cardiovascular risk management, including, as appropriate, lipidcontrol, diabetes management, antithrombotic therapy, smoking cessation, exercise,and limited sodium intake. Many patients will require more than 1 drug toachieve blood pressure goals. For specific advice on goals and management, seepublished guidelines, such as those of the National High Blood PressureEducation Program’s Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety ofpharmacologic classes and with different mechanisms of action, have been shownin randomized controlled trials to reduce cardiovascular morbidity andmortality, and it can be concluded that it is blood pressure reduction, and notsome other pharmacologic property of the drugs, that is largely responsible forthose benefits. The largest and most consistent cardiovascular outcome benefithas been a reduction in the risk of stroke, but reductions in myocardialinfarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increasedcardiovascular risk, and the absolute risk increase per mmHg is greater athigher blood pressures, so that even modest reductions of severe hypertensioncan provide substantial benefit. Relative risk reduction from blood pressurereduction is similar across populations with varying absolute risk, so theabsolute benefit is greater in patients who are at higher risk independent oftheir hypertension (for example, patients with diabetes or hyperlipidemia), andsuch patients would be expected to benefit from more aggressive treatment to a lowerblood pressure goal.

Some antihypertensive drugs have smaller blood pressureeffects (as monotherapy) in black patients, and many antihypertensive drugshave additional approved indications and effects (e.g., on angina, heart failure,or diabetic kidney disease). These considerations may guide selection oftherapy. Zestril may be administered alone or with other antihypertensiveagents [see Clinical Studies].

Heart Failure

Zestril is indicated to reduce signs and symptoms ofsystolic heart failure [see Clinical Studies].

Reduction Of Mortality In Acute Myocardial Infarction

Zestril is indicated for the reduction of mortality intreatment of hemodynamically stable patients within 24 hours of acute myocardialinfarction. Patients should receive, as appropriate, the standard recommendedtreatments such as thrombolytics, aspirin and beta-blockers [see ClinicalStudies].

Dosage for Zestril

Hypertension

Initial Therapy in adults: The recommended initialdose is 10 mg once a day. Dosage should be adjusted according to blood pressureresponse. The usual dosage range is 20 to 40 mg per day administered in asingle daily dose. Doses up to 80 mg have been used but do not appear to give greatereffect.

Use With Diuretics In Adults

If blood pressure is not controlled with Zestril alone, alow dose of a diuretic may be added (e.g., hydrochlorothiazide, 12.5 mg). Afterthe addition of a diuretic, it may be possible to reduce the dose of Zestril.

The recommended starting dose in adult patients withhypertension taking diuretics is 5 mg once per day.

Pediatric Patients 6 Years Of Age And Older With Hypertension

For pediatric patients with glomerular filtration rate > 30 mL/min/1.73m², the recommended starting dose is 0.07 mg per kg oncedaily (up to 5 mg total). Dosage should be adjusted according to blood pressureresponse up to a maximum of 0.61 mg per kg (up to 40 mg) once daily. Dosesabove 0.61 mg per kg (or in excess of 40 mg) have not been studied in pediatricpatients [see CLINICAL PHARMACOLOGY].

Zestril is not recommended in pediatric patients < 6years or in pediatric patients with glomerular filtration rate < 30mL/min/1.73m² [see Use in Specific Populations and Clinical Studies].

Heart Failure

The recommended starting dose for Zestril, when used withdiuretics and (usually) digitalis as adjunctive therapy for systolic heartfailure, is 5 mg once daily. The recommended starting dose in these patientswith hyponatremia (serum sodium < 130 mEq/L) is 2.5 mg once daily. Increaseas tolerated to a maximum of 40 mg once daily.

Diuretic dose may need to be adjusted to help minimizehypovolemia, which may contribute to hypotension [see WARNINGS ANDPRECAUTIONS, and DRUG INTERACTIONS]. The appearance of hypotensionafter the initial dose of Zestril does not preclude subsequent careful dosetitration with the drug, following effective management of the hypotension.

Reduction Of Mortality In Acute Myocardial Infarction

In hemodynamically stable patients within 24 hours of theonset of symptoms of acute myocardial infarction, give Zestril 5 mg orally,followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg oncedaily. Dosing should continue for at least six weeks.

Initiate therapy with 2.5 mg in patients with a lowsystolic blood pressure ( ≤ 120 mmHg and > 100 mmHg) during the first 3days after the infarct [see WARNINGS AND PRECAUTIONS]. If hypotension occurs(systolic blood pressure ≤ 100 mmHg) a daily maintenance dose of 5 mg maybe given with temporary reductions to 2.5 mg if needed. If prolongedhypotension occurs (systolic blood pressure < 90 mmHg for more than 1 hour)Zestril should be withdrawn.

Dose In Patients With Renal Impairment

No dose adjustment of Zestril is required in patientswith creatinine clearance > 30 mL/min. In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of Zestril tohalf of the usual recommended dose i.e., hypertension, 5 mg; systolic heartfailure, 2.5 mg and acute MI, 2.5 mg. Up titrate as tolerated to a maximum of40 mg daily. For patients on hemodialysis or creatinine clearance < 10mL/min, the recommended initial dose is 2.5 mg once daily [see Use inSpecific Populations and CLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

2.5 mg are white, round, biconvex, uncoated tabletsidentified as “ZESTRIL 2 ½” on one side and “135” on the other side.

5 mg are pink, capsule-shaped, biconvex, bisected,uncoated tablets identified as “ZESTRIL” on one side and “130” on the otherside.

10 mg are pink, round, biconvex, uncoated tabletsidentified as “ZESTRIL 10” on one side and “131” on the other side.

20 mg are red, round, biconvex, uncoated tabletsidentified as “ZESTRIL 20” on one side and “132” on the other side.

30 mg are red, round, biconvex, uncoated tabletsidentified as “ZESTRIL 30” on one side and “133” on the other side.

40 mg are yellow, round, biconvex, uncoated tabletsidentified as “ZESTRIL 40” on one side and “134” on the other side.

Storage And Handling

Zestril is available as uncoated biconvex tablets inbottles of 90 and bottles of 100.

Store at controlled room temperature, 20-25°C (68-77°F)[see USP]. Protect from moisture, freezing and excessive heat. Dispensein a tight container.

Manufactured by: AstraZeneca UK Limited, Macclesfield, UK.Distributed by: Almatica Pharma, Inc., Pine Brook, NJ 07058 USA. Revised: Mar 2015.

Side Effects for Zestril

Clinical Trials Experience

Because clinical trials are conducted under widelyvarying conditions, adverse reaction rates observed in the clinical studies ofa drug cannot be directly compared to rates in the clinical studies of another drugand may not reflect the rates observed in practice.

Hypertension

In clinical trials in patients with hypertension treatedwith Zestril, 5.7% of patients on Zestril discontinued with adverse reactions.

The following adverse reactions (events 2% greater onZestril than on placebo) were observed with Zestril alone: headache (by 3.8%),dizziness (by 3.5%), cough (by 2.5%).

Heart Failure

In patients with systolic heart failure treated withZestril for up to four years, 11% discontinued therapy with adverse reactions.In controlled studies in patients with heart failure, therapy was discontinuedin 8.1% of patients treated with Zestril for 12 weeks, compared to 7.7% ofpatients treated with placebo for 12 weeks.

The following adverse reactions (events 2% greater onZestril than on placebo) were observed with Zestril: hypotension (by 3.8%),chest pain (by 2.1%).

In the two-dose ATLAS trial [see Clinical Studies]in heart failure patients, withdrawals due to adverse reactions were notdifferent between the low and high groups, either in total number of discontinuation(17-18%) or in rare specific reactions ( < 1%). The following adversereactions, mostly related to ACE inhibition, were reported more commonly in thehigh dose group:

Table 1 : Dose-related Adverse Drug Reactions : ATLAStrial

Acute Myocardial Infarction

Patients treated with Zestril had a higher incidence ofhypotension (by 5.3%) and renal dysfunction (by 1.3%) compared with patientsnot taking Zestril.

Other clinical adverse reactions occurring in 1% orhigher of patients with hypertension or heart failure treated with Zestril incontrolled clinical trials and do not appear in other sections of labeling are listedbelow:

Body as a whole: Fatigue, asthenia, orthostaticeffects.

Digestive: Pancreatitis, constipation, flatulence,dry mouth, diarrhea.

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

Endocrine: Diabetes mellitus, inappropriateantidiuretic hormone secretion.

Metabolic: Gout.

Skin: Urticaria, alopecia, photosensitivity,erythema, flushing, diaphoresis, cutaneous pseudolymphoma, toxic epidermalnecrolysis, Stevens - Johnson syndrome, and pruritus.

Special Senses: Visual loss, diplopia, blurredvision, tinnitus, photophobia, taste disturbances, olfactory disturbance.

Urogenital: Impotence.

Miscellaneous: A symptom complex has been reportedwhich may include a positive ANA, an elevated erythrocyte sedimentation rate,arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, leukocytosis,paresthesia and vertigo. Rash, photosensitivity or other dermatologicalmanifestations may occur alone or in combination with these symptoms.

Clinical Laboratory Test Findings

Serum Potassium: In clinical trials hyperkalemia(serum potassium greater than 5.7 mEq/L) occurred in 2.2% and 4.8% ofZestril-treated patients with hypertension and heart failure, respectively [see WARNINGS AND PRECAUTIONS].

Creatinine, Blood Urea Nitrogen: Minor increasesin blood urea nitrogen and serum creatinine, reversible upon discontinuation oftherapy, were observed in about 2% of patients with hypertension treated withZestril alone. Increases were more common in patients receiving concomitantdiuretics and in patients with renal artery stenosis [see WARNINGS ANDPRECAUTIONS]. Reversible minor increases in blood urea nitrogen and serumcreatinine were observed in 11.6% of patients with heart failure on concomitantdiuretic therapy. Frequently, these abnormalities resolved when the dosage ofthe diuretic was decreased.

Patients with acute myocardial infarction in the GISSI-3trial treated with Zestril had a higher (2.4% versus 1.1% in placebo) incidenceof renal dysfunction in-hospital and at six weeks (increasing creatinineconcentration to over 3 mg/dL or a doubling or more of the baseline serumcreatinine concentration).

Hemoglobin and Hematocrit: Small decreases inhemoglobin and hematocrit (mean decreases of approximately 0.4 g% and 1.3 vol%,respectively) occurred frequently in patients treated with Zestril but wererarely of clinical importance in patients without some other cause of anemia.In clinical trials, less than 0.1% of patients discontinued therapy due toanemia.

Post-marketing Experience

The following adverse reactions have been identifiedduring post-approval use of Zestril that are not included in other sections oflabeling. Because these reactions are reported voluntarily from a population ofuncertain size, it is not always possible to reliably estimate their frequencyor establish a causal relationship to drug exposure.

Other reactions include:

Metabolism and Nutrition Disorders

Hyponatremia [see WARNINGS AND PRECAUTIONS], casesof hypoglycemia in diabetic patients on oral antidiabetic agents or insulin[see DRUG INTERACTIONS]

Nervous System and Psychiatric Disorders

Mood alterations (including depressive symptoms), mentalconfusion, hallucinations

Skin and Subcutaneous Tissue Disorders

Psoriasis

Drug Interactions for Zestril

Diuretics

Initiation of Zestril in patients on diuretics may resultin excessive reduction of blood pressure. The possibility of hypotensiveeffects with Zestril can be minimized by either decreasing or discontinuing thediuretic or increasing the salt intake prior to initiation of treatment withZestril. If this is not possible, reduce the starting dose of Zestril [see DOSAGEAND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Zestril attenuates potassium loss caused by thiazide-typediuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene,and others) can increase the risk of hyperkalemia. Therefore, if concomitantuse of such agents is indicated, monitor the patient's serum potassiumfrequently.

Antidiabetics

Concomitant administration of Zestril and antidiabeticmedicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-loweringeffect with risk of hypoglycemia.

Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenas e-2 Inhibitors (COX-2 Inhibitors )

In patients who are elderly, volume-depleted (includingthose on diuretic therapy), or with compromised renal function,coadministration of NSAIDs, including selective COX-2 inhibitors, with ACEinhibitors, including lisinopril, may result in deterioration of renalfunction, including possible acute renal failure. These effects are usuallyreversible. Monitor renal function periodically in patients receivinglisinopril and NSAID therapy.

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

Dual Blockade Of The Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptorblockers, ACE inhibitors, or aliskiren is associated with increased risks ofhypotension, hyperkalemia, and changes in renal function (including acute renalfailure) compared to monotherapy.

The VA NEPHRON trial enrolled 1448 patients with type 2diabetes, elevated urinary-albumin-tocreatinine ratio, and decreased estimatedglomerular filtration rate (GFR 30 to 89.9 ml/min), randomized them tolisinopril or placebo on a background of losartan therapy and followed them fora median of 2.2 years. Patients receiving the combination of losartan andlisinopril did not obtain any additional benefit compared to monotherapy forthe combined endpoint of decline in GFR, end state renal disease, or death, butexperienced an increased incidence of hyperkalemia and acute kidney injurycompared with the monotherapy group.

In general, avoid combined use of RAS inhibitors. Closelymonitor blood pressure, renal function and electrolytes in patients on Zestriland other agents that affect the RAS.

Do not co-administer aliskiren with Zestril in patientswith diabetes. Avoid use of aliskiren with Zestril in patients with renalimpairment (GFR < 60 ml/min).

Lithium

Lithium toxicity has been reported in patients receivinglithium concomitantly with drugs, which cause elimination of sodium, includingACE inhibitors. Lithium toxicity was usually reversible upon discontinuation oflithium and the ACE inhibitor. Monitor serum lithium levels during concurrentuse.

Gold

Nitritoid reactions (symptoms include facial flushing,nausea, vomiting and hypotension) have been reported rarely in patients ontherapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitortherapy including Zestril.

mTOR Inhibitors

Patients taking concomitant mTOR inhibitor (e.g.temsirolimus, sirolimus, everolimus) therapy may be at increased risk forangioedema. [see WARNINGS AND PRECAUTIONS]

Warnings for Zestril

Included as part of the PRECAUTIONS section.

Precautions for Zestril

Fetal Toxicity

Zestril can cause fetal harm when administered to apregnant woman. Use of drugs that act on the reninZestril can cause fetal harmwhen administered to a pregnant woman. Use of drugs that act on thereninangiotensin system during the second and third trimesters of pregnancyreduces fetal renal function and increases fetal and neonatal morbidity anddeath. Resulting oligohydramnios can be associated with fetal lung hypoplasiaand skeletal deformations. Potential neonatal adverse effects include skull hypoplasia,anuria, hypotension, renal failure, and death. When pregnancy is detected,discontinue Zestril as soon as possible [see Use in Specific Populations].

Angioedema And Anaphylactoid Reactions

Patients taking concomitant mTOR inhibitor (e.g.temsirolimus, sirolimus, everolimus) therapy may be at increased risk forangioedema. [see DRUG INTERACTIONS].

Angioedema

Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue,glottis and/or larynx, including some fatal reactions, have occurred inpatients treated with angiotensin converting enzyme inhibitors, includingZestril, at any time during treatment. Patients with involvement of the tongue,glottis or larynx are likely to experience airway obstruction, especially thosewith a history of airway surgery. Zestril should be promptly discontinued andappropriate therapy and monitoring should be provided until complete andsustained resolution of signs and symptoms of angioedema has occurred.

Patients with a history of angioedema unrelated to ACEinhibitor therapy may be at increased risk of angioedema while receiving an ACEinhibitor [see CONTRAINDICATIONS]. ACE inhibitors have been associatedwith a higher rate of angioedema in black than in non-black patients.

Intestinal Angioedema

Intestinal angioedema has occurred in patients treatedwith ACE inhibitors. These patients presented with abdominal pain (with orwithout nausea or vomiting); in some cases there was no prior history of facialangioedema and C-1 esterase levels were normal. In some cases, the angioedemawas diagnosed by procedures including abdominal CT scan or ultrasound, or atsurgery, and symptoms resolved after stopping the ACE inhibitor.

Anaphylactoid Reactions

Anaphylactoid Reactions During Desensitization

Two patients undergoing desensitizing treatment withhymenoptera venom while receiving ACE inhibitors sustained life- threateninganaphylactoid reactions.

Anaphylactoid Reactions During Dialysis

Sudden and potentially life threatening anaphylactoidreactions have occurred in some patients dialyzed with high-flux membranes andtreated concomitantly with an ACE inhibitor. In such patients, dialysis must bestopped immediately, and aggressive therapy for anaphylactoid reactions must beinitiated. Symptoms have not been relieved by antihistamines in thesesituations. In these patients, consideration should be given to using adifferent type of dialysis membrane or a different class of antihypertensive agent.Anaphylactoid reactions have also been reported in patients undergoinglow-density lipoprotein apheresis with dextran sulfate absorption.

Impaired Renal Function

Monitor renal function periodically in patients treatedwith Zestril. Changes in renal function including acute renal failure can becaused by drugs that inhibit the renin-angiotensin system. Patients whose renalfunction may depend in part on the activity of the renin-angiotensin system(e.g., patients with renal artery stenosis, chronic kidney disease, severecongestive heart failure, post-myocardial infarction or volume depletion) maybe at particular risk of developing acute renal failure on Zestril. Consider withholdingor discontinuing therapy in patients who develop a clinically significantdecrease in renal function on Zestril [see ADVERSE REACTIONS, DRUGINTERACTIONS].

Hypotension

Zestril can cause symptomatic hypotension, sometimes complicatedby oliguria, progressive azotemia, acute renal failure or death. Patients atrisk of excessive hypotension include those with the following conditions orcharacteristics: heart failure with systolic blood pressure below 100 mmHg,ischemic heart disease, cerebrovascular disease, hyponatremia, high dosediuretic therapy, renal dialysis, or severe volume and/or salt depletion of anyetiology.

In these patients, Zestril should be started under veryclose medical supervision and such patients should be followed closely for thefirst two weeks of treatment and whenever the dose of Zestril and/or diureticis increased. Avoid use of Zestril in patients who are hemodynamically unstableafter acute MI.

Symptomatic hypotension is also possible in patients withsevere aortic stenosis or hypertrophic cardiomyopathy.

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesiawith agents that produce hypotension, Zestril may block angiotensin IIformation secondary to compensatory renin release. If hypotension occurs and isconsidered to be due to this mechanism, it can be corrected by volumeexpansion.

Hyperkalemia

Serum potassium should be monitored periodically inpatients receiving Zestril. Drugs that inhibit the renin angiotensin system cancause hyperkalemia. Risk factors for the development of hyperkalemia includerenal insufficiency, diabetes mellitus, and the concomitant use ofpotassium-sparing diuretics, potassium supplements and/or potassium-containingsalt substitutes [see DRUG INTERACTIONS].

Hepatic Failure

ACE inhibitors have been associated with a syndrome thatstarts with cholestatic jaundice or hepatitis and progresses to fulminanthepatic necrosis and sometimes death. The mechanism of this syndrome is notunderstood. Patients receiving ACE inhibitors who develop jaundice or markedelevations of hepatic enzymes should discontinue the ACE inhibitor and receiveappropriate medical treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There was no evidence of a tumorigenic effect whenlisinopril was administered for 105 weeks to male and female rats at doses upto 90 mg per kg per day (about 56 or 9 times the maximum recommended dailyhuman dose, based on body weight and body surface area, respectively). Therewas no evidence of carcinogenicity when lisinopril was administered for 92weeks to (male and female) mice at doses up to 135 mg per kg per day (about 84times¹ the maximum recommended daily human dose). This dose was 6.8times the maximum human dose based on body surface area in mice.

Lisinopril was not mutagenic in the Ames microbial mutagentest with or without metabolic activation. It was also negative in a forwardmutation assay using Chinese hamster lung cells. Lisinopril did not producesingle strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay.In addition, lisinopril did not produce increases in chromosomal aberrations inan in vitro test in Chinese hamster ovary cells or in an in vivo study in mousebone marrow.

There were no adverse effects on reproductive performancein male and female rats treated with up to 300 mg per kg per day of lisinopril.This dose is 188 times and 30 times the maximum human dose when based on mg/kgand mg/m², respectively.

Studies in rats indicate that lisinopril crosses theblood brain barrier poorly. Multiple doses of lisinopril in rats do not resultin accumulation in any tissues. Milk of lactating rats contains radioactivity followingadministration of ¹⁴C lisinopril. By whole body autoradiography,radioactivity was found in the placenta following administration of labeleddrug to pregnant rats, but none was found in the fetuses.

¹Calculations assume a human weight of 50 kgand human body surface area of 1.62m²

Use In Specific Populations

Pregnancy

Risk Summary

Zestril can cause fetal harm when administered to apregnant woman. Use of drugs that act on the reninangiotensin system during thesecond and third trimesters of pregnancy reduces fetal renal function and increasesfetal and neonatal morbidity and death. Most epidemiologic studies examiningfetal abnormalities after exposure to antihypertensive use in the firsttrimester have not distinguished drugs affecting the renin-angiotensin systemfrom other antihypertensive agents. When pregnancy is detected, discontinueZestril as soon as possible.

The estimated background risk of major birth defects andmiscarriage for the indicated population(s) are unknown. In the general U.S.population, the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk forpre-eclampsia, gestational diabetes, premature delivery, and deliverycomplications (e.g., need for cesarean section, and post-partum hemorrhage).Hypertension increases the fetal risk for intrauterine growth restriction andintrauterine death. Pregnant women with hypertension should be carefullymonitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Oligohydramnios in pregnant women who use drugs affectingthe renin-angiotensin system in the second and third trimesters of pregnancycan result in the following: reduced fetal renal function leading to anuria andrenal failure, fetal lung hypoplasia and skeletal deformations, including skullhypoplasia, hypotension, and death. In the unusual case that there is noappropriate alternative to therapy with drugs affecting the renin-angiotensinsystem for a particular patient, apprise the mother of the potential risk to thefetus.

Perform serial ultrasound examinations to assess theintra-amniotic environment. Fetal testing may be appropriate, based on the weekof pregnancy. Patients and physicians should be aware, however, that oligohydramniosmay not appear until after the fetus has sustained irreversible injury. Closelyobserve infants with histories of in utero exposure to Zestril for hypotension,oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with ahistory of in utero exposure to Zestril, support blood pressure and renalperfusion. Exchange transfusions or dialysis may be required as a means of reversinghypotension and substituting for disordered renal function.

Lactation

Risk Summary

No data are available regarding the presence oflisinopril in human milk or the effects of lisinopril on the breast fed infantor on milk production. Lisinopril is present in rat milk. Because of thepotential for severe adverse reactions in the breastfed infant, advise womennot to breastfeed during treatment with Zestril.

Pediatric Use

Antihypertensive effects and safety of Zestril have beenestablished in pediatric patients aged 6 to 16 years [see DOSAGE ANDADMINISTRATION and Clinical Studies]. No relevant differencesbetween the adverse reaction profile for pediatric patients and adult patientswere identified.

Safety and effectiveness of Zestril have not beenestablished in pediatric patients under the age 6 or in pediatric patients withglomerular filtration rate < 30 mL/min/1.73 m² [see DOSAGE ANDADMINISTRATION, CLINICAL PHARMACOLOGY, and Clinical Studies].

Neonates With A History Of In Utero Exposure To Zestril

If oliguria or hypotension occurs, direct attentiontoward support of blood pressure and renal perfusion. Exchange transfusions ordialysis may be required as a means of reversing hypotension and/orsubstituting for disordered renal function.

Geriatric Use

No dosage adjustment with Zestril is necessary in elderlypatients. In a clinical study of Zestril in patients with myocardialinfarctions (GISSI-3 Trial) 4,413 (47%) were 65 and over, while 1,656 (18%) were75 and over. In this study, 4.8 % of patients aged 75 years and olderdiscontinued Zestril treatment because of renal dysfunction vs. 1.3% ofpatients younger than 75 years. No other differences in safety or effectivenesswere observed between elderly and younger patients, but greater sensitivity ofsome older individuals cannot be ruled out.

Race

ACE inhibitors, including Zestril, have an effect onblood pressure that is less in black patients than in non blacks.

Renal Impairment

Dose adjustment of Zestril is required in patientsundergoing hemodialysis or whose creatinine clearance is ≤ 30 mL/min. Nodose adjustment of Zestril is required in patients with creatinine clearance >30 mL/min [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Overdose Information for Zestril

Following a single oral dose of 20 g/kg no lethalityoccurred 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 theusual treatment would be intravenous infusion of normal saline solution.

Lisinopril can be removed by hemodialysis [see CLINICALPHARMACOLOGY].

Contraindications for Zestril

Zestril is contraindicated in patients with:

• a history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme inhibitor
• hereditary or idiopathic angioedema

Do not co-administer aliskiren with ZESTRIL in patientswith diabetes [see DRUG INTERACTIONS]

Clinical Pharmacology for Zestril

Mechanism Of Action

Lisinopril inhibits angiotensin-converting enzyme (ACE)in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes theconversion of angiotensin I to the vasoconstrictor substance, angiotensin II.Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Thebeneficial effects of lisinopril in hypertension and heart failure appear toresult primarily from suppression of the renin-angiotensin-aldosterone system.Inhibition of ACE results in decreased plasma angiotensin II which leads todecreased vasopressor activity and to decreased aldosterone secretion. Thelatter decrease may result in a small increase of serum potassium. Inhypertensive patients with normal renal function treated with Zestril alone forup to 24 weeks, the mean increase in serum potassium was approximately 0.1mEq/L; however, approximately 15% of patients had increases greater than 0.5mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the samestudy, patients treated with Zestril and hydrochlorothiazide for up to 24 weekshad a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% ofpatients had increases greater than 0.5 mEq/L and approximately 12% had adecrease greater than 0.5 mEq/L [see Clinical Studies]. Removal ofangiotensin II negative feedback on renin secretion leads to increased plasmarenin activity.

ACE is identical to kininase, an enzyme that degradesbradykinin. Whether increased levels of bradykinin, a potent vasodepressorpeptide, play a role in the therapeutic effects of Zestril remains to be elucidated.

While the mechanism through which Zestril lowers bloodpressure is believed to be primarily suppression of therenin-angiotensin-aldosterone system, Zestril is antihypertensive even inpatients with low-renin hypertension. Although Zestril was antihypertensive inall races studied, Black hypertensive patients (usually a low-reninhypertensive population) had a smaller average response to monotherapy than nonBlack patients.

Concomitant administration of Zestril andhydrochlorothiazide further reduced blood pressure in Black and non-Blackpatients and any racial differences in blood pressure response were no longerevident.

Pharmacodynamics

Hypertension

Adult Patients: Administration of Zestril topatients with hypertension results in a reduction of both supine and standingblood pressure to about the same extent with no compensatory tachycardia. Symptomaticpostural hypotension is usually not observed although it can occur and shouldbe anticipated in volume and/or salt-depleted patients [see WARNINGS ANDPRECAUTIONS]. When given together with thiazide-type diuretics, the bloodpressure lowering effects of the two drugs are approximately additive.

In most patients studied, onset of antihypertensiveactivity was seen at one hour after oral administration of an individual doseof Zestril, with peak reduction of blood pressure achieved by 6 hours. Althoughan antihypertensive effect was observed 24 hours after dosing with recommendedsingle daily doses, the effect was more consistent and the mean effect wasconsiderably larger in some studies with doses of 20 mg or more than with lowerdoses; however, at all doses studied, the mean antihypertensive effect wassubstantially smaller 24 hours after dosing than it was 6 hours after dosing.

The antihypertensive effects of Zestril are maintainedduring long-term therapy. Abrupt withdrawal of Zestril has not been associatedwith a rapid increase in blood pressure, or a significant increase in bloodpressure compared to pretreatment levels.

Non-Steroidal Anti-Inflammatory Agents

In a study in 36 patients with mild to moderatehypertension where the antihypertensive effects of Zestril alone were comparedto Zestril given concomitantly with indomethacin, the use of indomethacin was associatedwith a reduced effect, although the difference between the two regimens was notsignificant.

Pharmaco*kinetics

Adult Patients: Following oral administration ofZestril, peak serum concentrations of lisinopril occur within about 7 hours,although there was a trend to a small delay in time taken to reach peak serum concentrationsin acute myocardial infarction patients. Food does not alter thebioavailability of Zestril. Declining serum concentrations exhibit a prolongedterminal phase, which does not contribute to drug accumulation. This terminalphase probably represents saturable binding to ACE and is not proportional todose. Upon multiple dosing, lisinopril exhibits an effective half-life of 12hours.

Lisinopril does not appear to be bound to other serumproteins. Lisinopril does not undergo metabolism and is excreted unchangedentirely in the urine. Based on urinary recovery, the mean extent of absorptionof lisinopril is approximately 25%, with large intersubject variability (6-60%)at all doses tested (5-80 mg). The absolute bioavailability of lisinopril isreduced to 16% in patients with stable NYHA Class II-IV congestive heartfailure, and the volume of distribution appears to be slightly smaller thanthat in normal subjects. The oral bioavailability of lisinopril in patientswith acute myocardial infarction is similar to that in healthy volunteers.

Impaired renal function decreases elimination oflisinopril, which is excreted principally through the kidneys, but thisdecrease becomes clinically important only when the glomerular filtration rateis below 30 mL/min. Above this glomerular filtration rate, the eliminationhalf-life is little changed. With greater impairment, however, peak and troughlisinopril levels increase, time to peak concentration increases and time toattain steady state is prolonged [see DOSAGE AND ADMINISTRATION].Lisinopril can be removed by hemodialysis.

Pediatric Patients: The pharmaco*kinetics oflisinopril were studied in 29 pediatric hypertensive patients between 6 yearsand 16 years with glomerular filtration rate > 30 mL/min/1.73 m . Afterdoses of 0.1 to 0.2 mg per kg, steady state peak plasma concentrations oflisinopril occurred within 6 hours and the extent of absorption based onurinary recovery was about 28%. These values are similar to those obtainedpreviously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolutebioavailability) in a child weighing 30 kg is 10 L/h, which increases inproportion to renal function. In a multicenter, open-label pharmaco*kineticstudy of daily oral lisinopril in 22 pediatric hypertensive patients withstable kidney transplant (ages 7-17 years; estimated glomerular filtration rate > 30 mL/min/1.73 m²), dose normalized exposures were in the range reportedpreviously in children without a kidney transplant.

Clinical Studies

Hypertension

Two dose-response studies utilizing a once-daily regimenwere conducted in 438 mild to moderate hypertensive patients not on a diuretic.Blood pressure was measured 24 hours after dosing. An antihypertensive effectof Zestril was seen with 5 mg of Zestril in some patients. However, in both studiesblood pressure reduction occurred sooner and was greater in patients treatedwith 10, 20 or 80 mg of Zestril than patients treated with 5 mg of Zestril.

In controlled clinical studies of patients with mild tomoderate hypertension, patients were treated with Zestril 20-80 mg daily,hydrochlorothiazide 12.5-50 mg daily or atenolol 50-200 mg daily; and in other studiesof patients with moderate to severe hypertension, patients were treated withZestril 20-80 mg daily or metoprolol 100-200 mg daily. Zestril demonstratedsuperior reductions of systolic and diastolic compared to hydrochlorothiazidein a population that was 75% Caucasian. Zestril was approximately equivalent toatenolol and metoprolol in reducing diastolic blood pressure, and had somewhatgreater effects on systolic blood pressure.

Zestril had similar blood pressure reductions and adverseeffects in younger and older ( > 65 years) patients. It was less effective inreducing blood pressure in Blacks than in Caucasians.

In hemodynamic studies of Zestril in patients withessential hypertension, blood pressure reduction was accompanied by a reductionin peripheral arterial resistance with little or no change in cardiac output andin heart rate. In a study in nine hypertensive patients, followingadministration of Zestril, there was an increase in mean renal blood flow thatwas not significant. Data from several small studies are inconsistent withrespect to the effect of lisinopril on glomerular filtration rate inhypertensive patients with normal renal function, but suggest that changes, ifany, are not large.

In patients with renovascular hypertension Zestril hasbeen shown to be well tolerated and effective in reducing blood pressure [see WARNINGSAND PRECAUTIONS].

Pediatric Patients: In a clinical study involving115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 50 kg received either 0.625, 2.5 or 20 mg of Zestril once daily andpatients who weighed ≥ 50 kg received either 1.25, 5, or 40 mg of Zestrilonce daily. At the end of 2 weeks, Zestril lowered trough blood pressure in adose-dependent manner with antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg per kg). This effect was confirmed in a randomized withdrawalphase, where the diastolic pressure rose by about 9 mmHg more in patientsrandomized to placebo than compared to patients who remained on the middle andhigh doses of lisinopril. The dosedependent antihypertensive effect of Zestrilwas consistent across several demographic subgroups: age, Tanner stage, gender,and race. In this study, lisinopril was generally well-tolerated.

In the above pediatric studies, Zestril was given eitheras tablets or in a suspension for those children and infants who were unable toswallow tablets or who required a lower dose than is available in tablet form[see DOSAGE AND ADMINISTRATION].

Heart Failure

In two placebo controlled, 12-week clinical studiescompared the addition of Zestril up to 20 mg daily to digitalis and diureticsalone. The combination of Zestril, digitalis and diuretics reduced the followingsigns and symptoms of heart failure: edema, rales, paroxysmal nocturnal dyspneaand jugular venous distention. In one of the studies, the combination ofZestril, digitalis and diuretics reduced orthopnea, presence of third heartsound and the number of patients classified as NYHA Class III and IV; andimproved exercise tolerance. A large (over 3000 patients) survival study, theATLAS Trial, comparing 2.5 and 35 mg of lisinopril in patients with systolicheart failure, showed that the higher dose of lisinopril had outcomes at leastas favorable as the lower dose.

During baseline-controlled clinical trials, in patientswith systolic heart failure receiving digitalis and diuretics, single doses ofZestril resulted in decreases in pulmonary capillary wedge pressure, systemicvascular resistance and blood pressure accompanied by an increase in cardiacoutput and no change in heart rate.

Acute Myocardial Infarction

The Gruppo Italiano per lo Studio della Sopravvienza nell'InfartoMiocardico (GISSI-3) study was a multicenter, controlled, randomized, unblindedclinical trial conducted in 19,394 patients with acute myocardial infarction(MI) admitted to a coronary care unit. It was designed to examine the effectsof short-term (6 week) treatment with lisinopril, nitrates, their combination,or no therapy on short-term (6 week) mortality and on long-term death andmarkedly impaired cardiac function. Hemodynamicallystable patients presentingwithin 24 hours of the onset of symptoms were randomized, in a 2 x 2 factorial design,to six weeks of either 1) Zestril alone (n=4841), 2) nitrates alone (n=4869),3) Zestril plus nitrates (n=4841), or 4) open control (n=4843). All patientsreceived routine therapies, including thrombolytics (72%), aspirin (84%), and abeta blocker (31%), as appropriate, normally utilized in acute myocardialinfarction (MI) patients.

The protocol excluded patients with hypotension (systolicblood pressure ≤ 100 mmHg), severe heart failure, cardiogenic shock, andrenal dysfunction (serum creatinine > 2 mg per dL and/or proteinuria > 500mg per 24 h). Patients randomized to Zestril received 5 mg within 24 hours ofthe onset of symptoms, 5 mg after 24 hours, and then 10 mg daily thereafter.Patients with systolic blood pressure less than 120 mmHg at baseline received2.5 mg of Zestril. If hypotension occurred, the Zestril dose was reduced or ifsevere hypotension occurred Zestril was stopped [see DOSAGE ANDADMINISTRATION].

The primary outcomes of the trial were the overallmortality at 6 weeks and a combined end point at 6 months after the myocardialinfarction, consisting of the number of patients who died, had late (day 4) clinicalcongestive heart failure, or had extensive left ventricular damage defined asejection fraction ≤ 35% or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving Zestril (n=9646), alone or with nitrates, had an 11%lower risk of death (p = 0.04) compared to patients who did not receive Zestril(n=9672) (6.4% vs. 7.2%, respectively) at six weeks. Although patientsrandomized to receive Zestril for up to six weeks also fared numerically betteron the combined end point at 6 months, the open nature of the assessment ofheart failure, substantial loss to follow-up echocardiography, and substantial excessuse of Zestril between 6 weeks and 6 months in the group randomized to 6 weeksof lisinopril, preclude any conclusion about this end point.

Patients with acute myocardial infarction, treated withZestril, had a higher (9.0% versus 3.7%) incidence of persistent hypotension(systolic blood pressure < 90 mmHg for more than 1 hour) and renaldysfunction (2.4% versus 1.1%) in-hospital and at six weeks (increasingcreatinine concentration to over 3 mg per dL or a doubling or more of thebaseline serum creatinine concentration) [see ADVERSE REACTIONS].

Patient Information for Zestril

NOTE: This information is intended to aid in thesafe and effective use of this medication. It is not a disclosure of allpossible adverse or intended effects.

Pregnancy

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider with a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Angioedema

Angioedema, including laryngeal edema may occur at any time during treatment with angiotensin converting enzyme inhibitors, including Zestril. Tell patients 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.

Lactation

Advise women not to breastfeed during treatment with Zestril [see Use in Specific Populations]

Symptomatic Hypotension

Tell patients to report light-headedness especially during the first few days of therapy. If actual syncope occurs, tell the patient to discontinue the drug until they have consulted with the prescribing physician.

Tell patients that excessive perspiration and dehydrationmay lead to an excessive fall in blood pressure because of reduction in fluidvolume. Other causes of volume depletion such as vomiting or diarrhea may alsolead to a fall in blood pressure; advise patients accordingly.

Hyperkalemia

Tell patients not to use salt substitutes containing potassium without consulting their physician.

Hypoglycemia

Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor to monitor for hypoglycaemia closely, especially during the first month of combined use [see DRUG INTERACTIONS].

Leukopenia/Neutropenia

Tell patients to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign of leukopenia/neutropenia.