Zestril (Lisinopril)

ZESTRIL®

Zeneca

Lisinopril

Angiotensin Converting Enzyme Inhibitor

Action And Clinical Pharmacology: Lisinopril is an ACE inhibitor which is used in the treatment of hypertension, congestive heart failure and following myocardial infarction in hemodynamically stable patients.

Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion. Although the latter decrease is small, it results in a small increase in serum K. In patients treated with lisinopril and a thiazide diuretic there was essentially no change in serum potassium.

ACE is identical to kininase II. Thus, lisinopril may also block the degradation of bradykinin, a potent vasodilator peptide. However, the role that this plays in the therapeutic effects of lisinopril is unknown.

While the mechanism through which lisinopril lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, lisinopril also lowers blood pressure in patients with low-renin hypertension. However, black hypertensive patients (usually a low-renin hypertensive population) have a smaller average response to lisinopril monotherapy than nonblack patients.

Administration of lisinopril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of lisinopril, the onset of antihypertensive activity is seen at 1 hour with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing. On occasion, achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy.

In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study of 9 hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

When lisinopril is given together with thiazide-type diuretics, its blood pressure lowering effect is approximately additive.

The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in nonblacks patients.

Administration of lisinopril to patients with congestive heart failure reduces afterload and preload of the heart, resulting in an increase in cardiac output, without reflex tachycardia. Exercise tolerance is improved.

Pharmacokinetics: After oral administration of lisinopril, peak serum concentrations of lisinopril occur within approximately 7 hours, although patients with recent myocardial infarction have demonstrated an increase in time to peak serum concentration to about 8 to 10 hours. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not bind serum proteins other than ACE.

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the extent of absorption of lisinopril is approximately 25%, with large inter-subject variability (6 to 60%) at all doses tested (5 to 80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract.

Following multiple doses of lisinopril, the effective half-life of accumulation is 12 hours.

In a study in elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations and higher values for the area under the plasma curve than those seen in young healthy adults given a similar dose. In another study, single daily doses of lisinopril 5 mg were given for 7 consecutive days to young and elderly healthy volunteers and to elderly patients with congestive heart failure. Maximum serum concentrations of lisinopril on Day 7 were higher in the elderly volunteers than in the young, and still higher in the elderly patients with congestive heart failure. Renal clearance of lisinopril was decreased in the elderly, particularly in the presence of congestive heart failure.

Impaired renal function decreases elimination of lisinopril. This decrease becomes clinically important when the glomerular filtration rate is below 30 mL/min (see Precautions, Impaired Renal Function and Dosage).

Lisinopril can be removed by dialysis.

Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.

Indications And Clinical Uses:

• Hypertension: Lisinopril is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with thiazide diuretics. A great majority of patients (>80%) with severe hypertension required combination therapy. Lisinopril has been used concomitantly with beta-blockers and calcium antagonists, but the data on such use are limited. Lisinopril should normally be used in those patients in whom treatment with diuretic or beta-blocker was found ineffective or has been associated with unacceptable adverse effects. Lisinopril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects;
• Heart Failure: Lisinopril is indicated in the management of symptomatic congestive heart failure as adjunctive treatment with diuretics, and where appropriate, digitalis. Treatment with lisinopril should be initiated under close medical supervision, usually in a hospital;
• Acute Myocardial Infarction: Lisinopril is indicated in the treatment of hemodynamically stable patients within 24 hours of an acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, ASA and beta-blocker(s). Therapy with lisinopril should be reassessed after 6 weeks. If there is no evidence of symptomatic or asymptomatic left ventricular dysfunction, treatment with lisinopril can be stopped. Lisinopril should not be used if systolic blood pressure is less than 100 mmHg, if clinically relevant renal failure is present, if there is a history of bilateral stenosis of the renal arteries, or if there is a known allergy to ACE inhibitors (see Precautions, Hypotension in Acute Myocardial Infarction, Renal Impairment);
• Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected lisinopril should be discontinued as soon as possible (see Warnings, Pregnancy and Precautions, Information for the Patient). In using lisinopril, attention should be given to the risk of angioedema (see Warnings).

Contra-Indications: In patients who are hypersensitive to this product and in patients with a history of angioneurotic edema relating to previous treatment with an angiotensin-converting enzyme inhibitor.

Manufacturers’ Warnings In Clinical States:

Angioedema: Angioedema has been reported in patients treated with lisinopril. Angioedema associated with laryngeal edema and/or shock may be fatal. If angioedema occurs, lisinopril should be promptly discontinued and the patient should be observed until the swelling subsides. Where swelling is confined to the face, lips and mouth the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, s.c. epinephrine (0.5 mL 1:1 000) should be administered promptly when indicated.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in nonblack patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).

Hypotension: Symptomatic hypotension has occurred after administration of lisinopril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, vomiting, or possibly in patients with renin-dependent renovascular hypertension (see Dosage). In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision, usually in a hospital. Such patients should be followed closely for the first 2 weeks of treatment and whenever the dose of lisinopril and/or diuretic is increased. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see Adverse Effects).

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an i.v. infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion.

In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with lisinopril. If hypotension occurs, a reduction of dose or discontinuation of therapy should be considered.

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by angiotensin converting enzyme inhibitors. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.

Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, lisinopril should be discontinued as soon as possible.

In rare cases (probably less than once in every thousand pregnancies) in which no alternative to ACE inhibitor therapy will be found, the mothers should be apprised of the potential hazards to their fetuses. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, then lisinopril should be discontinued unless it is considered life saving for the mother. A nonstress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending on the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with a history 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 a means of reversing hypotension and/or substituting for imparied renal function, however, limited experience with those procedures has not been associated with significant clinical benefit.

Lisinopril has been removed from the neonatal circulation by peritoneal dialysis.

Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. 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 and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

Animal Data: Lisinopril was not teratogenic in mice treated on days 6 to 15 of gestation with up to 1 000 mg/kg/day (625 times the maximum recommended human dose). There was an increase in fetal resorptions at doses down to 100 mg/kg; at doses of 1 000 mg/kg, this was prevented by saline supplementation. There was no fetotoxicity or teratogenicity in rats treated with up to 300 mg/kg/day (188 times the maximum recommended dose) of lisinopril at days 6 to 17 of gestation. In rats receiving lisinopril from day 15 of gestation through day 21 postpartum, there was an increased incidence in pup deaths on days 2 to 7 postpartum and a lower average body weight of pups on day 21 postpartum. The increase in pup deaths and decrease in pup weight did not occur with maternal saline supplementation.

Lisinopril, at doses up to 1 mg/kg/day, was not teratogenic when given throughout the organogenic period in saline supplemented rabbits. Saline supplementation (physiologic saline in place of tap water) was used to eliminate maternotoxic effects and enable evaluation of the teratogenic potential at the highest possible dosage level. The rabbit has been shown to be extremely sensitive to angiotensin converting enzyme inhibitors (captopril and enalapril) with maternal and fetotoxic effects apparent at or below the recommended therapeutic dosage levels in man.

Fetotoxicity was demonstrated in rabbits by an increased incidence of fetal resorptions at an oral dose of lisinopril of 1 mg/kg/day and by an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg/kg/day). A single i.v. dose of 15 mg/kg of lisinopril administered to pregnant rabbits on gestation days 16, 21 or 26 resulted in 88 to 100% fetal death.

By whole body autoradiography, radioactivity was found in the placenta following administration of labeled lisinopril to pregnant rats, but none was found in the fetuses.

Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 µmol/L and/or proteinuria exceeding 500 mg/24 h. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 265 µmol/L or a doubling from the pre-treatment value), then the physician should consider withdrawal of lisinopril.

Use of lisinopril should include appropriate assessment of renal function.

Hypotension in Acute Myocardial Infarction: Treatment with lisinopril must not be initiated in patients with acute myocardial infarction who are at risk of further serious hemodynamic deterioration after treatment with a vasodilator. These include patients with systolic blood pressure of 100 mmHg or lower or those in cardiogenic shock.

During the first 3 days following the infarction, dosage reduction should occur if systolic blood pressure is between 100 and 120 mmHg (see Dosage, Acute Myocardial Infarction).

Patients with myocardial infarction in the GISSI-3 study treated with lisinopril, had a higher (9.0% vs 3.7%) incidence of persistent hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour) than placebo.

Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g.: polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid Reactions During Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Hyperkalemia: In clinical trials hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 2.2% of hypertensive patients and 4% of patients with congestive heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1% of hypertensive patients. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes.

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril blocks angiotensin II formation, secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Patients with Impaired Liver Function: Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with lisinopril, in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Should the patient receiving lisinopril experience any unexplained symptoms (see Information for the Patient), particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of lisinopril should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Lisinopril should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Cough: A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of lisinopril, has been reported.

Such possibility should be considered as part of the differential diagnosis of the cough.

Lactation: Milk of lactating rats contains radioactivity following administration of 4 lisinopril.

It is not known whether this drug is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when lisinopril is given to a nursing mother.

Children: Safety and effectiveness in children have not been established.

Drug Interactions: Hypotension: Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with lisinopril. The possibility of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to initiation of treatment with lisinopril and/or lowering the initial dose of lisinopril.

Agents Increasing Serum Potassium: Since lisinopril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and with frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Potassium-containing salt substitutes should also be used with caution.

Agents Causing Renin Release: The antihypertensive effect of lisinopril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to lisinopril.

Indomethacin: Indomethacin may diminish the antihypertensive efficacy of concomitantly administered lisinopril.

Lithium Salts: As with other drugs which eliminate sodium, lithium elimination may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of lisinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.

Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include ‘viral-like symptoms’ in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Pregnancy: Since the use of lisinopril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Note: As with many other drugs, certain advice to patients being treated with lisinopril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Adverse Reactions: In controlled clinical trials involving 3 269 patients (2 633 patients with hypertension and 636 patients with congestive heart failure), the most frequent clinical adverse reactions were: dizziness (4.4%), headache (5.6%), asthenia/fatigue (2.7%), diarrhea (1.8%) and cough (3.0%), all of which were more frequent than in placebo-treated patients. Discontinuation of therapy was required in 5.9% of patients.

For adverse reactions which occurred in hypertensive patients and patients with congestive heart failure treated with lisinopril in controlled clinical trials, comparative incidence data are listed in Table I.

Angioedema: Angioedema has been reported in patients receiving lisinopril (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with lisinopril should be discontinued and appropriate therapy instituted immediately.

Hypotension: In hypertensive patients, hypotension occurred in 0.8% and syncope occurred in 0.2% of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.3% of hypertensive patients.

In patients with congestive heart failure, hypotension occurred in 5.2% and syncope occurred in 1.7% of patients. Hypotension and dizziness were causes for discontinuation of therapy in 1.7% of these patients.

Additional adverse reactions which occurred rarely, either during controlled clinical trials or after the drug was marketed, include: Cardiovascular: myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients, tachycardia.

Gastrointestinal: abdominal pain, dry mouth, pancreatitis.

Hepatic: liver function abnormalities, hepatitis, jaundice (hepatocellular and/or cholestatic).

Nervous System: mood alterations, mental confusion.

Respiratory: bronchospasm.

Dermatologic: alopecia, diaphoresis, pemphigus, pruritus, Stevens-Johnson syndrome, urticaria.

Hematologic: hemolytic anemia.

Special Senses: taste disorders.

Urogenital: uremia, oliguria/anuria, renal dysfunction, acute renal failure, impotence.

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity, or other dermatologic manifestations may also occur.

Laboratory Test Findings: Serum Electrolytes: Hyperkalemia.

Creatinine, Blood Urea Nitrogen: Increases in blood urea nitrogen and serum creatinine, usually reversible upon discontinuation of therapy, were observed in 1.1 and 1.6% of patients respectively with essential hypertension treated with lisinopril alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (see Precautions). Reversible increases in blood urea nitrogen (14.5%) and serum creatinine (11.2%) were observed in approximately 12.0% of patients with congestive heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.

Hematology: Decreases in hemoglobin and hematocrit (mean decreases of approximately 0.9 g% and 0.6 vol%, respectively) occurred frequently in patients treated with lisinopril but were rarely of clinical importance in patients without some other cause of anemia.

An occasional case of neutropenia and bone marrow depression has been reported in the world literature.

Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred.

Discontinuations: Overall, 1.0% of patients discontinued therapy due to laboratory adverse experiences, principally elevations in blood urea nitrogen (0.8%), serum creatinine (0.1%) and serum potassium (0.1%).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There are no data on overdosage in humans. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be i.v. infusion of normal saline solution.

Lisinopril may be removed from the general circulation by hemodialysis.

Dosage And Administration: Since absorption of lisinopril is not affected by food, the tablets may be administered before, during or after meals. Lisinopril should be administered in a single daily dose.

Dosage must be individualized.

Essential Hypertension: In patients with essential hypertension, not on diuretic therapy, the usual recommended starting dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response: the usual dosage range is 10 to 40 mg/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. The maximum dose used in long-term controlled clinical trials was 80 mg/day. If blood pressure is not controlled with lisinopril alone, a low dose of diuretic may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the addition of diuretic, it may be possible to reduce the dose of lisinopril.

Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of lisinopril. The diuretic should be discontinued, if possible, for 2 to 3 days before beginning therapy with lisinopril to reduce the likelihood of hypotension (see Warnings). The dosage of lisinopril should be adjusted according to blood pressure response. If the patient’s blood pressure is not controlled with lisinopril 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 2 hours and until blood pressure has stabilized for at least an additional hour.

A lower starting dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued, patients who are volume and/or salt-depleted for any reason, and in patients with renovascular hypertension.

Dosage Adjustment in Renal Impairment: Dosage in patients with renal impairment should be based on creatinine clearance as outlined in Table II.

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g.: polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor.

Renovascular Hypertension: Some patients with renovascular hypertension, especially those with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, may develop an exaggerated response to the first dose of lisinopril. Therefore, a lower starting dose of 2.5 or 5 mg is recommended. Thereafter, the dosage may be adjusted according to the blood pressure response.

Geriatrics: In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of lisinopril. 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.

Congestive Heart Failure: Lisinopril is to be used in conjunction with diuretics, and where appropriate digitalis. Therapy must be initiated under close medical supervision, usually in a hospital. Blood pressure and renal function should be monitored, both before and during treatment with lisinopril, because severe hypotension and, more rarely, consequent renal failure have been reported.

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment.

The recommended initial dose is 2.5 mg/day. If required, the dose should be increased gradually, depending on the patient response. The usual effective dosage range is 5 to 20 mg/day administered in a single daily dose. Dose titration may be performed over a 2 to 4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure.

Acute Myocardial Infarction: Treatment with lisinopril may be started within 24 hours of the onset of symptoms in hemodynamically stable patients. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, ASA and beta-blocker(s).

The first dose of lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter.

Patients with a low systolic blood pressure (between 100 and 120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower dose – 2.5 mg orally (see Precautions, Hypotension and Acute Myocardial Infarction). After 3 days if hypotension occurs (systolic blood pressure less than or equal to 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 less than 90 mmHg for more than 1 hour), lisinopril should be withdrawn.

Renal function should be assessed before and during therapy with lisinopril.

Dosing should normally continue for 6 weeks. At that time, patients with signs or symptoms of heart failure should continue with lisinopril.

Lisinopril is compatible with i.v. or transdermal glyceryl trinitrate.

Availability And Storage: 5 mg: Each pale pink, round, biconvex tablet, scored on one side and embossed with the number 5 inside a heart-shaped symbol on the other side, contains: lisinopril 5 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, cornstarch, magnesium stearate, mannitol, pregelatinized cornstarch and red iron oxide. Bottles of 100 and 500 and calendar packs of 30.

10 mg: Each pale pink, round, biconvex tablet, embossed with the number 10 and “ZESTRIL” inside a heart-shaped symbol on one side and blank on the other side, contains: lisinopril 10 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, cornstarch, magnesium stearate, mannitol, pregelatinized cornstarch and red iron oxide. Bottles of 100 and 500 and calendar packs of 30.

20 mg: Each deep pink, round, biconvex tablet, embossed with the number 20 and “ZESTRIL” inside a heart-shaped symbol on one side and blank on the other side contains: lisinopril 20 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, cornstarch, magnesium stearate, mannitol, pregelatinized cornstarch and red iron oxide. Bottles of 100 and 500 and calendar packs of 30.

Store at room temperature.

ZESTRIL® Zeneca Lisinopril Angiotensin Converting Enzyme Inhibitor

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