Zestril

Zestril

lisinopril

Manufacturer:

AstraZeneca

Distributor:

Zuellig
Full Prescribing Info
Contents
Anhydrous lisinopril.
Description
Each tablet contains lisinopril dihydrate equivalent to 5 mg, 10 mg or 20 mg of anhydrous lisinopril.
List of excipients: (MF 2575) Mannitol Ph. Eur., Calcium Hydrogen Phosphate Ph. Eur., Red Iron Oxide (E172), Yellow iron oxide (in 40 mg tablets) (E172), Maize Starch Ph. Eur., Pregelatinized Starch Ph. Eur., Magnesium Stearate Ph. Eur.
Action
Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors. ATC code: C09AA03.
Pharmacology: Pharmacodynamics: Lisinopril (ZESTRIL) is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion. The latter decrease may result in an increase in serum potassium concentration.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.
The effect of Lisinopril (ZESTRIL) on mortality and morbidity in congestive heart failure has been studied by comparing a high dose (32.5 mg or 35 mg once daily) with a low dose (2.5 mg or 5 mg once daily). In a study of 3164 patients, with a median follow up period of 46 months for surviving patients, high dose Lisinopril (ZESTRIL) produced a 12% risk reduction in the combined endpoint of all-cause mortality and all-cause hospitalization (p = 0.002) and an 8% risk reduction in all-cause mortality and cardiovascular hospitalization (p = 0.036) compared with low dose. Risk reductions for all-cause mortality (8%; p = 0.128) and cardiovascular mortality (10%; p = 0.073) were observed. In a post-hoc analysis, the number of hospitalizations for heart failure was reduced by 24% (p = 0.002) in patients treated with high-dose Lisinopril (ZESTRIL) compared with low dose. Symptomatic benefits were similar in patients treated with high and low doses of Lisinopril (ZESTRIL).
The results of the study showed that the overall adverse event profiles for patients treated with high or low dose Lisinopril (ZESTRIL) were similar in both nature and number. Predictable events resulting from ACE inhibition, such as hypotension or altered renal function, were manageable and rarely led to treatment withdrawal. Cough was less frequent in patients treated with high dose Lisinopril (ZESTRIL) compared with low dose.
In the GISSI-3 trial, which used a 2 x 2 factorial design to compare the effects of Lisinopril (ZESTRIL) and glyceryl trinitrate given alone or in combination for 6 weeks versus control in 19,394, patients who were administered the treatment within 24 hours of an acute myocardial infarction, Lisinopril (ZESTRIL) produced a statistically significant risk reduction in mortality of 11% versus control (2p = 0.03). The risk reduction with glyceryl trinitrate was not significant but the combination of Lisinopril (ZESTRIL) and glyceryl trinitrate produced a significant risk reduction in mortality of 17% versus control (2p = 0.02). In the sub-groups of elderly (age > 70 years) and females, pre-defined as patients at high risk of mortality, significant benefit was observed for a combined endpoint of mortality and cardiac function. The combined endpoint for all patients, as well as the high-risk sub-groups, at 6 months also showed significant benefit for those treated with Lisinopril (ZESTRIL) or Lisinopril (ZESTRIL) plus glyceryl trinitrate for 6 weeks, indicating a prevention effect for Lisinopril (ZESTRIL). As would be expected from any vasodilator treatment, increased incidences of hypotension and renal dysfunction were associated with Lisinopril (ZESTRIL) treatment but these were not associated with a proportional increase in mortality.
In a double-blind, randomized, multicentre trial which compared Lisinopril (ZESTRIL) with a calcium channel blocker in 335 hypertensive Type 2 diabetes mellitus subjects with incipient nephropathy characterized by microalbuminuria, Lisinopril (ZESTRIL) 10 mg to 20 mg administered once daily for 12 months, reduced systolic/diastolic blood pressure by 13/10 mmHg and urinary albumin excretion rate by 40%. When compared with the calcium channel blocker, which produced a similar reduction in blood pressure, those treated with Lisinopril (ZESTRIL) showed a significantly greater reduction in urinary albumin excretion rate, providing evidence that the ACE inhibitory action of Lisinopril (ZESTRIL) reduced microalbuminuria by a direct mechanism on renal tissues in addition to its blood pressure lowering effect.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycemia. ACE inhibitors, including lisinopril, inhibit the formation of angiotensin II and breakdown of bradykinin and hence ameliorate endothelial dysfunction.
The effects of Lisinopril on urinary albumin excretion rate in diabetic patients is mediated by a reduction in blood pressure as well as a direct mechanism on the renal and retinal tissues.
In a clinical study involving 115 hypertensive pediatric patients aged 6 to 16 years, patients who weighed less than 50 kg received either 0.625 mg, 2.5 mg or 20 mg of Lisinopril (ZESTRIL) once a day, and patients who weighed 50 kg or more received either 1.25 mg, 5 mg or 40 mg of Lisinopril (ZESTRIL) once a day. At the end of 2 weeks, Lisinopril (ZESTRIL) administered once daily lowered trough blood pressure in a dose-dependent manner with a consistent antihypertensive efficacy demonstrated at doses greater than 1.25 mg.
This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mm Hg more in patients randomized to placebo that it did in patients who were randomized to remain on the middle and high doses of Lisinopril. The dose-dependent antihypertensive effect of Lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, and race.
Pharmacokinetics: Lisinopril is an orally active non-sulphydryl-containing ACE inhibitor.
Absorption: Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with inter-patient variability 6-60% over the dose range studied (5-80 mg). The absolute bioavailability is reduced to approximately 16% in patients with heart failure. Lisinopril absorption is not affected by the presence of food.
Distribution: Lisinopril does not appear to be bound to serum proteins other than to circulating angiotensin converting enzyme (ACE). Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.
Elimination: Lisinopril does not undergo metabolism and is excreted entirely unchanged into the urine. On multiple dosing lisinopril has an effective half-life of accumulation of 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 mL/min. 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.
Hepatic impairment: Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril absorption (about 30% as determined by urinary recovery) but an increase in exposure (approximately 50%) compared to healthy subjects due to decreased clearance.
Renal impairment: Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. (See Table 1.)

Click on icon to see table/diagram/image

With a creatinine clearance of 30-80 mL/min, mean AUC was increased by 13% only, while a 4-5 fold increase in mean AUC was observed with a creatinine clearance of 5-30 mL/min.
Lisinopril can be removed by dialysis. During 4 hours of hemodialysis, plasma lisinopril concentrations decreased on average by 60%, with a dialysis clearance between 40 and 55 mL/min.
Heart failure: Patients with heart failure have a greater exposure of lisinopril when compared to healthy subjects (an increase in AUC on average of 125%), but based on the urinary recovery of lisinopril, there is reduced absorption of approximately 16% compared to healthy subjects.
Elderly: Older patients have higher blood levels and higher values for the area under the plasma concentration time curve (increased approximately 60%) compared with younger subjects.
Pediatric patients: The pharmacokinetic profile of Lisinopril was studied in 29 pediatric hypertensive patients, aged between 6 and 16 years, with a GFR above 30 mL/min/1.73m2. After doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of Lisinopril occurred within 6 hours, and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults.
The typical value of Lisinopril oral clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 101/h, which increases in proportion to renal function.
AUC and Cmax values in children in this study were consistent with those observed in adults.
Toxicology: Preclinical safety data: Lisinopril is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Prescribing Information.
Indications/Uses
Hypertension: Lisinopril (ZESTRIL) is indicated in the treatment of hypertension and in renovascular hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.
Congestive Heart failure: Lisinopril (ZESTRIL) is indicated in the management of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis. High doses reduce the risk of the combined outcomes of mortality and hospitalization.
Acute myocardial infarction: Lisinopril (ZESTRIL) is indicated for the treatment of hemodynamically stable patients within 24 hours of an acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers.
Renal complications of diabetes mellitus: In normotensive insulin-dependent and hypertensive non-insulin-dependent diabetes mellitus patients who have incipient nephropathy characterized by microalbuminuria, Lisinopril (ZESTRIL) reduces urinary albumin excretion rate.
Dosage/Direction for Use
Lisinopril (ZESTRIL) should be administered orally in a single daily dose. As with all other medication taken once daily, Lisinopril (ZESTRIL) should be taken at approximately the same time each day. The absorption of Lisinopril (ZESTRIL) tablets is not affected by food. The tablets may be administered before, during or after meals.
The dose should be adjusted according to blood pressure response.
Hypertension: In patients with hypertension the usual recommended starting dose is 10 mg.
The usual effective maintenance dosage is 20 mg administered in a single daily dose. In general if the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks on a certain dose level, the dose can be further increased. The maximum dose used in long-term, controlled clinical trials was 80 mg/day.
A lower starting dose is required in the presence of renal impairment (see Table 2), 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.
Diuretic-treated patients: Symptomatic hypotension may occur following initiation of therapy with Lisinopril (ZESTRIL). This is more likely in patients who are being treated currently with diuretics. Caution is recommended, therefore, since these patients may be volume and/or salt depleted. The diuretic should be discontinued 2 to 3 days before beginning therapy with Lisinopril (ZESTRIL) (see Precautions). In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Lisinopril (ZESTRIL) should be initiated with a 5 mg dose. The subsequent dosage of Lisinopril (ZESTRIL) should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.
Dosage adjustment in renal impairment: Dosage in patients with renal impairment should be based on creatinine clearance as outlined in Table 2 as follows. (See Table 2.)

Click on icon to see table/diagram/image

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
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 (ZESTRIL). Therefore, a lower starting dose of 2.5 mg or 5 mg is recommended. Thereafter, the dosage may be adjusted according to the blood pressure response.
Congestive Heart failure: As adjunctive therapy to diuretics and, where appropriate, digitalis. Lisinopril (ZESTRIL) may be initiated at a starting dose of 2.5 mg once a day. To reduce the risk of the combined outcomes of mortality and hospitalization the dose of Lisinopril (ZESTRIL) should be increased: By increments of no greater than 10 mg; At intervals of no less than 2 weeks; To the highest dose tolerated by the patient up to a maximum of 35 mg once daily.
Dose adjustment should be based on the clinical response of individual patients. Patients at high risk of symptomatic hypotension e.g. patients with salt depletion with or without hyponatremia, patients with hypovolemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with Lisinopril (ZESTRIL). The effect of the starting dose of Lisinopril (ZESTRIL) on blood pressure should be monitored carefully.
Acute myocardial infarction: Treatment with Lisinopril (ZESTRIL) may be started within 24 hours of the onset of symptoms. The first dose of Lisinopril (ZESTRIL) 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 (120 mmHg or less) when treatment is started or during the first 3 days after the infarction should be given a lower dose - 2.5 mg orally (see Precautions).
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 (ZESTRIL) should be withdrawn.
Dosing should continue for 6 weeks. Patients who develop symptoms of heart failure should continue with Lisinopril (ZESTRIL) (see as previously mentioned).
Lisinopril (ZESTRIL) is compatible with intravenous or transdermal glyceryl trinitrate.
Renal complications of diabetes mellitus: In normotensive insulin-dependent diabetes mellitus patients, the daily dose is 10 mg Lisinopril (ZESTRIL) once daily which can be increased to 20 mg once daily, if necessary, to achieve a sitting diastolic blood pressure below 75 mmHg. In hypertensive non-insulin-dependent diabetes mellitus patients, the dose schedule is as previously mentioned to achieve a sitting diastolic blood pressure below 90 mmHg.
Pediatric use: There are limited data on efficacy, safety and pharmacokinetics in hypertensive children and adolescents aged 6-16 years (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
The recommended initial dose is 2.5 mg once daily in patients 20 to <50 kg, and 5 mg once daily in patients ≥50 kg. The dosage should be individually adjusted to a maximum of 20 mg daily in patients weighing 20 to <50 kg, and 40 mg in patients ≥50 kg. Doses in excess of 40 mg have not been studied in pediatric patients.
Lisinopril (ZESTRIL) is not recommended in children below the age of 6, or in children with severe renal impairment (GFR <30 mL/min/1.73m2).
Use in the elderly: In clinical studies, there was no age-related change in the efficacy or safety profile of the drug. When advanced age is associated with decrease in renal function, however, the guidelines set out in Table 2 (previously mentioned) should be used to determine the starting dose of Lisinopril (ZESTRIL). Thereafter, the dosage should be adjusted according to the blood pressure response.
Overdosage
The symptoms of overdosage may include severe hypotension, electrolyte disturbance and renal failure. After ingestion of an overdose, the patient should be kept under very close supervision. Therapeutic measures depend on the nature and severity of the symptoms. Measures to prevent absorption and methods to speed elimination should be employed. If severe hypotension occurs, the patient should be placed in the shock position and an intravenous infusion of normal saline should be given rapidly. If available, treatment with angiotensin II may be considered. ACE inhibitors may be removed from the circulation by hemodialysis. The use of high-flux polyacrylonitrile dialysis membranes should be avoided. Serum electrolytes and creatinine concentrations should be monitored frequently.
Contraindications
Lisinopril (ZESTRIL) is contraindicated: In patients who are Hypersensitive to any component of this product.
In patients with a history of anaphylactic/anaphylactoid reactions or angioedema relating to previous treatment with an angiotensin-converting enzyme (ACE) inhibitor.
In patients with hereditary or idiopathic angioedema.
In second or third trimesters of pregnancy (see Use in Pregnancy & Lactation).
In combination with aliskiren-containing medicines in patients with diabetes mellitus (Type I or II) or with moderate to severe renal impairment (GFR <60mL/min/1.73m2).
Special Precautions
Symptomatic hypotension: Symptomatic hypotension was seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Lisinopril (ZESTRIL), hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting. In patients with congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatremia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be monitored under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
As with other vasodilators, Lisinopril (ZESTRIL) should be given with caution to patients with aortic stenosis or hypertrophic cardiomyopathy.
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Lisinopril (ZESTRIL). This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Lisinopril (ZESTRIL) may be necessary.
Hypotension in acute myocardial infarction: Treatment with Lisinopril (ZESTRIL) must not be initiated in acute myocardial infarction patients who are at risk of further serious hemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mmHg or lower or cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mmHg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than 1 hour) then Lisinopril (ZESTRIL) should be withdrawn.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Contraindications and Precautions).
If dual blockade therapy is considered necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Lisinopril (ZESTRIL) may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Renal function impairment: In patients with congestive heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the previously mentioned, they should be discontinued and renal function should be monitored during the first weeks of Lisinopril (ZESTRIL) therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Lisinopril (ZESTRIL) has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Lisinopril (ZESTRIL) may be required.
In acute myocardial infarction, treatment with Lisinopril (ZESTRIL) should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/L and/or proteinuria exceeding 500 mg/24 h. If renal dysfunction develops during treatment with Lisinopril (ZESTRIL) (serum creatinine concentration exceeding 265 micromol/L or a doubling from the pre-treatment value) then the physician should consider withdrawal of Lisinopril (ZESTRIL).
Hypersensitivity/Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been uncommonly reported in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril (ZESTRIL). This may occur at any time during therapy. In such cases, Lisinopril (ZESTRIL) should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. 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. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
ACE inhibitors cause a higher rate of angioedema in black patients than in non-black 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).
Some drugs if given concomitantly with ACE inhibitors may increase the risk of angioedema (see Interactions).
Diabetic patients: In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored during the first month of treatment with Lisinopril (ZESTRIL) (see Interactions).
Hemodialysis patients: Anaphylactoid reactions have been reported in patients undergoing certain hemodialysis procedures (e.g. with the high flux membrane AN 69 and during low-density lipoproteins (LDL) apheresis with dextran sulfate) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.
Desensitization: Patients receiving ACE inhibitors during desensitization treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent rechallenge.
Race: ACE inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
ACE inhibitors may have a lesser effect on blood pressure in black-hypertensive patients than in non-black hypertensive patients.
Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Effects on Ability to Drive and Use Machines: When driving vehicles or operating machines it should be taken into account that dizziness or tiredness may occur.
Use In Pregnancy & Lactation
Pregnancy: Lisinopril (ZESTRIL) is contraindicated during the second and third trimesters of pregnancy (see Contraindications). The use of Lisinopril (ZESTRIL) is not recommended during the first trimester of pregnancy. When pregnancy is detected, lisinopril should be discontinued as soon as possible.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters. Use of ACE inhibitors during this period has been associated with fetal and neonatal injury including hypotension, renal failure, hyperkalemia and/or skull hypoplasia in the newborn. Maternal oligohydramnios, presumably representing decreased fetal renal function, has occurred and may result in limb contracture, craniofacial deformations and hypoplastic lung development.
Should exposure to Lisinopril (ZESTRIL) have occurred during the second or third trimester of pregnancy, serial ultrasound examinations should be performed to assess the intra-amniotic environment. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants should be closely observed for hypotension, oliguria and hyperkalemia. Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion.
These adverse effects to the embryo and fetus do not appear to have resulted from intrauterine ACE-inhibitor exposure limited to the first trimester. A retrospective epidemiological study has suggested that maternal exposure to an ACE inhibitor during the first trimester of pregnancy may lead to an increased risk of malformations, particularly of the cardiovascular and central nervous systems. If lisinopril is used during the first trimester of pregnancy, the patient should be informed of the potential hazard to the fetus.
Lactation: It is not known whether Lisinopril (ZESTRIL) is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised if Lisinopril (ZESTRIL) is given to women who are breast-feeding.
Adverse Reactions
Clinical trials: Lisinopril (ZESTRIL) has been found in controlled clinical trials to be generally well-tolerated. For the most part, side effects were mild and transient in nature.
The most frequent clinical side effects of Lisinopril (ZESTRIL) in controlled trials were: dizziness, headache, diarrhea, fatigue, cough and nausea. Other side effects occurring less frequently were: orthostatic effects (including hypotension), rash and asthenia.
In patients with congestive heart failure, high doses of Lisinopril (ZESTRIL) may predispose to symptoms related to hypotension (dizziness, syncope) and to biochemical changes related to impaired renal function (hyperkalemia and increased serum creatinine) as would be expected with ACE inhibitor therapy.
Safety data from clinical studies suggest that lisinopril is generally well tolerated in hypertensive pediatric patients, and that the safety profile in this age group is comparable to that seen in adults.
Post marketing: The following undesirable effects have been observed and reported during treatment with Lisinopril (ZESTRIL) with the following frequencies: Very common (≥10%), common (≥1%, <10%), uncommon (≥0.1, <1%), rare (≥0.01, <0.1%), very rare (<0.01%) including isolated reports.
Blood and the lymphatic system disorders: Very rare: bone marrow depression, anemia, thrombocytopenia, leucopenia, agranulocytosis, hemolytic anemia.
Immune system disorders: Not known: anaphylactic/anaphylactoid reaction.
Endocrine disorders: Rare: inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders: Uncommon: hyperkalemia. Rare: hyponatremia. Very rare: hypoglycemia.
Nervous system and psychiatric disorders: Common: dizziness, headache. Uncommon: mood alterations (including depressive symptoms), paresthesia, vertigo, taste disturbance, sleep disturbances, hallucinations. Rare: mental confusion, olfactory disturbance.
Cardiac and vascular disorders: Common: orthostatic effects (including hypotension). Uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Precautions), palpitations, tachycardia, syncope*.
* Frequency refers to hypertensive patient population. Frequency in congestive heart failure patient population is "common".
Respiratory, thoracic and mediastinal disorders: Common: cough. Uncommon: rhinitis. Very rare: bronchospasm, sinusitis.
Gastrointestinal disorders: Common: diarrhea, vomiting. Uncommon: nausea, abdominal pain and indigestion. Rare: dry mouth. Very rare: pancreatitis, intestinal angioedema.
Hepatobiliary disorders: Very rare: hepatitis-either hepatocellular or cholestatic, jaundice. Hepatic failure. Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving Lisinopril (ZESTRIL) who develop jaundice or marked elevation of hepatic enzymes should discontinue Lisinopril (ZESTRIL) and receive appropriate medical follow up.
Skin and subcutaneous tissue disorders: Uncommon: rash, pruritus, hypersensitivity/angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis, and/or larynx. Rare: urticaria, alopecia, psoriasis. Very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma.
A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.
Renal and urinary disorders: Common: renal dysfunction. Rare: uremia, acute renal failure. Very rare: oliguria/anuria.
Reproductive system and breast disorders: Uncommon: impotence.
General disorders and administration site conditions: Uncommon: fatigue, asthenia.
Investigations: Uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes. Rare: decreases in hemoglobin, decreases in hematocrit, increases in serum bilirubin.
Drug Interactions
Antihypertensive agents: When combined with other antihypertensive agents, additive falls in blood pressure may occur. Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Contraindications and Precautions).
Drugs that may increase the risk of angioedema: Concomitant treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) or tissue plasminogen activator may increase the risk of angioedema.
Diuretics: When a diuretic is added to the therapy of a patient receiving Lisinopril (ZESTRIL) the antihypertensive effect is usually additive.
Patients already on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when Lisinopril (ZESTRIL) is added. The possibility of symptomatic hypotension with Lisinopril (ZESTRIL) can be minimized by discontinuing the diuretic prior to initiation of treatment with Lisinopril (ZESTRIL) (see Dosage & Administration and Precautions).
Antidiabetics: Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Potassium supplements, potassium-sparing agents or potassium-containing salt substitutes and other drugs that may increase serum potassium levels: Although in clinical trials, serum potassium usually remained within normal limits, hyperkalemia did occur in some patients. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes and other drugs that may increase serum potassium levels (e.g. heparin, co-trimoxazole).
The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes and other drugs that may increase serum potassium levels, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium.
If concomitant use of Lisinopril (ZESTRIL) and any of the previously-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
If Lisinopril (ZESTRIL) is given with a potassium-losing diuretic, diuretic-induced hypokalemia may be ameliorated.
Lithium: As with other drugs which eliminate sodium, lithium elimination may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are administered.
Gold: Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.
Other Concomitant Therapy: Indomethacin may diminish the antihypertensive efficacy of concomitantly administered Lisinopril (ZESTRIL). In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs (NSAIDs), the co-administration of Lisinopril may result in a further deterioration in renal function.
Lisinopril (ZESTRIL) has been used concomitantly with nitrates without evidence of clinically significant adverse interactions.
Caution For Usage
Incompatibilities: None known.
Instructions for use, handling and disposal: No special instructions.
Storage
Store at a temperature not exceeding 30°C.
ATC Classification
C09AA03 - lisinopril ; Belongs to the class of ACE inhibitors. Used in the treatment of cardiovascular disease.
Presentation/Packing
Tab (pink, round and biconvex; marked on one side with a number denoting the tablet strength) 5 mg x 98's. 10 mg x 98's. 20 mg x 98's.
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