Lisinopril abrupt withdrawal - FDA Homepage

Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Pregnancy Lisinopril and Hydrochlorothiazide: Maternal or fetotoxic effects were not seen in mice with the combination. Associated with the decreased fetal weight was a delay in fetal ossification. When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Lisinopril and Hydrochlorothiazide Tablets should be discontinued as soon as possible.

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitor therapy should be discontinued as soon as possible. In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor drug during the first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs.

The number of cases of birth defects is small and the findings of this study have not yet been repeated. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed.

Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of Lisinopril and Hydrochlorothiazide Tablets as soon as possible. Rarely probably less often than once in every thousand pregnancies , no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, Lisinopril and Hydrochlorothiazide Tablets should be discontinued unless it is considered lifesaving for the mother.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia.

If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Lisinopril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure. No teratogenic effects of lisinopril were seen in studies of pregnant rats, mice, rabbits.

Hydrochlorothiazide given in a two-litter study in rats at doses of 4 - 5. Thiazides cross the placental barrier and appear in cord blood. These may include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions have occurred in the adult.

Hydrochlorothiazide Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported. As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. In such patients renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when lisinopril has been given concomitantly with a diuretic.

This is more likely to occur in patients with pre-existing renal impairment. Evaluation of the hypertensive patient should always include assessment of renal function. In clinical trials hyperkalemia serum potassium greater than 5. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy.

Hyperkalemia can cause serious, sometimes fatal, arrhythmias. Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, almost always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

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

Hydrochlorothiazide Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.

Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis e.

Although any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances as in liver disease or renal disease , chloride replacement may be required in the treatment of metabolic alkalosis.

Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of Lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system.

Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0. In the same study, patients treated with Lisinopril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lisinopril remains to be elucidated.

Although Lisinopril was antihypertensive in all races studied, Black hypertensive patients usually a low-renin hypertensive population had a smaller average response to monotherapy than non Black patients. Concomitant administration of Lisinopril and hydrochlorothiazide further reduced blood pressure in Black and non-Black patients and any racial differences in blood pressure response were no longer evident.

Administration of Lisinopril to patients with hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.

In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of Lisinopril, with peak reduction of blood pressure achieved by 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.

The antihypertensive effects of Lisinopril are maintained during long-term therapy. Following oral administration of Lisinopril, 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 concentrations in acute myocardial infarction patients. Food does not alter the bioavailability of Lisinopril. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation.

Upon multiple dosing, Lisinopril exhibits an effective half-life of 12 hours. Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine.

The oral bioavailability of Lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers. With greater impairment, however, peak and trough Lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged [see Dosage and Administration 2.

Lisinopril can be removed by hemodialysis. After doses of 0. These values are similar to those obtained previously in adults. This dose was 6. Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay.

In addition, Lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow. There were no adverse effects on reproductive performance in male and female rats treated with up to mg per kg per day of Lisinopril.

Studies in rats indicate that Lisinopril crosses the blood brain barrier poorly. Multiple doses of Lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C Lisinopril.

By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses. Blood pressure was measured 24 hours after dosing. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10 mg, 20 mg or 80 mg of Lisinopril than patients treated with 5 mg of Lisinopril.

In controlled clinical studies of patients with mild to moderate hypertension, patients were treated with Lisinopril 20 mg to 80 mg daily, hydrochlorothiazide 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. 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. 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. Lisinopril can be removed by dialysis. Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Indications And Clinical Uses: Lisinopril is indicated in the treatment of essential hypertension and in renovascular hypertension.

It may be used alone or concomitantly with thiazide diuretics. 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 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 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. 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. Angioedema has been reported in patients treated with lisinopril. 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. 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. 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.

Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision, usually in a hospital. 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. 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. 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.

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. 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.

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