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Prinivil

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Prinivil

Warnings
Precautions

WARNINGS

Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL. This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. In such cases PRINIVIL should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided. (See ADVERSE REACTIONS.)

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).

Intestinal Angioedema

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure: Sudden and potentially life-threatening anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g., AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hypotension

Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL alone.

Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with peak blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. (See DOSAGE AND ADMINISTRATION.)

Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high-dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with PRINIVIL in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See PRECAUTIONS: DRUG INTERACTIONS, and ADVERSE REACTIONS.)

Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus 3.7 percent) incidence of persistent hypotension (systolic blood pressure < 90 mmHg for more than 1 hour) when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute myocardial infarction patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.

In patients at risk of excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of PRINIVIL which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of PRINIVIL or concomitant diuretic may be necessary.

Leukopenia/Neutropenia/Agranulocytosis

Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of PRINIVIL are insufficient to show that PRINIVIL does not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue PRINIVIL as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative therapy to drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue PRINIVIL, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to PRINIVIL for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).

No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats, and rabbits. On a body surface area basis, the doses used were 55 times, 33 times, and 0.15 times, respectively, the maximum recommended human daily dose (MRHDD).

PRECAUTIONS

General

Aortic Stenosis/Hypertrophic Cardiomyopathy

As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including PRINIVIL, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of PRINIVIL and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.

Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when PRINIVIL 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 PRINIVIL may be required.

Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a higher (2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal of PRINIVIL.

Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)

Hyperkalemia

In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with 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 percent of hypertensive patients, 0.6 percent of patients with heart failure and 0.1 percent of patients with myocardial infarction. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. PRINIVIL should be used cautiously, if at all, with these agents and with frequent monitoring of serum potassium. (See DRUG INTERACTIONS.)

Cough

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

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, PRINIVIL 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105 weeks to male and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female mice at doses up to 135 mg/kg/day. These doses are 10 times and 7 times, respectively, the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.

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 300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).

Nursing Mothers

Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known whether this drug is secreted in human milk. Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision should be made whether to discontinue nursing or discontinue PRINIVIL, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to PRINIVIL

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.

Antihypertensive effects of PRINIVIL have been established in hypertensive pediatric patients aged 6 to 16 years.

There are no data on the effect of PRINIVIL on blood pressure in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m² (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects, and DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of PRINIVIL in patients with hypertension and congestive heart failure did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience in this population has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In a clinical study of PRINIVIL in patients with myocardial infarctions 4413 (47 percent) were 65 and over, while 1656 (18 percent) were 75 and over. No overall differences in safety or efficacy were observed between elderly and younger patients.

Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pharmacokinetic studies indicate that maximum blood levels and area under plasma concentration time curve (AUC) are doubled in elderly patients.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of patients with hypertension, congestive heart failure, or myocardial infarction should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)

Last reviewed on RxList: 3/20/2013
This monograph has been modified to include the generic and brand name in many instances.

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