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| {{DrugProjectFormSinglePage
| | #REDIRECT [[Enalapril]] |
| |authorTag={{AZ}}, {{AM}}
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| |genericName=Epaned, Vasotec, Vaseretic
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| |aOrAn=an
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| |drugClass=Angiontensin converting enzyme inhibitor
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| |indication=[[hypertension]], [[heart failure]], left ventricular dysfunction after [[myocardial infarction]], [[diabetic nephropathy]]
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| |hasBlackBoxWarning=Yes
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| |adverseReactions=[[Hyperkalemia]] (1% to 3.8% ), [[dizziness]] (4.3% to 7.9% ), increase in serum blood urea nitrogen (0.2% to 11% ), increase in serum [[creatinine]] (0.2% to 11% ), [[fatigue]] (3% )
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| |blackBoxWarningTitle=USE IN PREGNANCY
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| |blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> 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, enalapril maleate should be discontinued as soon as possible.
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| |fdaLIADAdult=<h4>Condition 1</h5>
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| * Dosing Information
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| :: (Dosage)
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| |warnings=====Anaphylactoid and Possibly Related Reactions====
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| * Presumably because [[angiotensin-converting enzyme inhibitors]] affect the metabolism of [[eicosanoids]] and polypeptides, including endogenous [[bradykinin]], patients receiving ACE inhibitors (including enalaprilat) may be subject to a variety of adverse reactions, some of them serious.
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| ====Head and Neck Angioedema====
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| * [[Angioedema]] of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalaprilat. This may occur at any time during treatment. In such cases enalaprilat should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with [[laryngeal edema]] may be fatal. 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).
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| ====Intestinal Angioedema====
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| * [[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.
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| ====Anaphylactoid reactions during desensitization====
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| * 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.
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| ====Anaphylactoid reactions during membrane exposure====
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| * Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing [[low-density lipoprotein]] apheresis with dextran sulfate absorption.
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| ====Hypotension====
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| * Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalaprilat alone. Patients with heart failure given enalaprilat commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. Patients at risk for 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]], [[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 enalaprilat in patients at risk for excessive hypotension who are able to tolerate such adjustments. In patients at risk for 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 enalapril and/or diuretic is increased. Similar considerations may 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]].
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| * 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 enalaprilat, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalaprilat or concomitant [[diuretic]] may be necessary.
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| ====Neutropenia/Agranulocytosis====
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| * 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 enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of [[neutropenia]] or [[agranulocytosis]] in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.
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| ====Hepatic Failure====
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| * Rarely, ACE inhibitors have been associated with a syndrome that starts with [[cholestatic jaundice]] 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.
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| ====Fetal/Neonatal Morbidity and Mortality====
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| * 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 inhibitors should be discontinued as soon as possible.
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| * In a published restrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their 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.
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| * 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.
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| * 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 enalaprilat as soon as possible.
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| * 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.
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| * If [[oligohydramnios]] is observed, enalaprilat should be discontinued unless it is considered lifesaving for the mother. [[Contraction stress testing]] ([[CST]]), a [[non-stress test]] ([[NST]]), or [[biophysical profiling]] ([[BPP]]) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
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| * 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. Exchange transfusion or [[dialysis]] may be required as means of reversing hypotension and/or substituting for disordered renal function. Enalapril, 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.
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| * No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD).
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| |clinicalTrials=b kj* Enalaprilat has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. enalaprilat has been found to be generally well tolerated in controlled clinical trials involving 2987 patients.
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| * For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with [[heart failure]]. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with enalaprilat reporting adverse experiences was comparable to placebo.
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| ====Hypertension====
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| * Adverse experiences occurring in greater than one percent of patients with hypertension treated with enalaprilat in controlled clinical trials are shown below. In patients treated with enalaprilat, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks.
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| [[File:Enalaprilat_injection_Adverse_Reaction008.png|800px|thumb]]
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| ====Heart Failure====
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| * Adverse experiences occurring in greater than one percent of patients with [[heart failure]] treated with enalaprilat are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). In the placebo treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with enalaprilat and placebo, respectively.
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| [[File:009.png|800px|thumb]]
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| * Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with [[hypertension]] or [[heart failure]] in clinical trials are listed below and, within each category, are in order of decreasing severity.
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| * Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions).
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| ====Cardiovascular====
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| * [[Cardiac arrest]]; [[myocardial infarction]] or [[cerebrovascular accident]], possibly secondary to excessive [[hypotension]] in high risk patients (see WARNINGS, Hypotension); [[pulmonary embolism]] and [[infarction]]; [[pulmonary edema]]; rhythm disturbances including [[atrial tachycardia]] and [[bradycardia]]; [[atrial fibrillation]]; [[palpitation]], [[Raynaud's phenomenon]].
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| ====Digestive====
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| * [[Ileus]], [[pancreatitis]], [[hepatic failure]], [[hepatitis]] (hepatocellular [proven on rechallenge] or [[cholestatic jaundice]]) (see WARNINGS, Hepatic Failure), [[melena]], [[anorexia]], [[dyspepsia]], [[constipation]], [[glossitis]], [[stomatitis]], [[dry mouth]].
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| ====Hematologic====
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| * Rare cases of [[neutropenia]], [[thrombocytopenia]] and [[bone marrow depression]].
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| ====Musculoskeletal====
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| * [[Muscle cramps]]
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| ====Nervous/Psychiatric====
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| * [[Depression]], [[confusion]], [[ataxia]], [[somnolence]], [[insomnia]], [[nervousness]], [[peripheral neuropathy]] (e.g., [[paresthesia]], [[dysesthesia]]), dream abnormality.
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| ====Respiratory====
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| * [[Bronchospasm]], [[rhinorrhea]], [[sore throat]] and [[hoarseness]], [[asthma]], [[upper respiratory infection]], [[pulmonary infiltrates]], [[eosinophilic pneumonitis]].
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| ====Skin====
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| * [[Exfoliative dermatitis]], [[toxic epidermal necrolysis]], [[Stevens-Johnson syndrome]], [[pemphigus]], [[herpes zoster]], [[erythema multiforme]], [[urticaria]], [[pruritus]], [[alopecia]], [[flushing]], [[diaphoresis]], [[photosensitivity]].
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| ====Special Senses====
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| * [[Blurred vision]], taste alteration, [[anosmia]], [[tinnitus]], [[conjunctivitis]], [[dry eyes]], tearing.
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| ====Urogenital====
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| * [[Renal failure]], [[oliguria]], [[renal dysfunction]] (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, [[gynecomastia]], [[impotence]].
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| ====Miscellaneous====
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| * A symptom complex has been reported which may include some or all of the following: a positive [[ANA]], an elevated [[erythrocyte sedimentation rate]], [[arthralgia]]/[[arthritis]], [[myalgia]]/[[myositis]], [[fever]], [[serositis]], [[vasculitis]], [[leukocytosis]], [[eosinophilia]], [[photosensitivity]], [[rash]] and other dermatologic manifestations.
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| ====Angioedema====
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| * [[Angioedema]] has been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately (see WARNINGS).
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| ====Hypotension====
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| * In the hypertensive patients, [[hypotension]] occurred in 0.9 percent and [[syncope]] occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see WARNINGS).
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| ====Fetal/Neonatal Morbidity and Mortality====
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| * See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
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| ====Cough====
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| ====Pediatric Patients====
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| * The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
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| ====Clinical Laboratory Test Findings====
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| ====Serum Electrolytes====
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| * [[Hyperkalemia]] (see PRECAUTIONS), [[hyponatremia]].
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| ====Creatinine, Blood Urea Nitrogen====
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| * In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalaprilat alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with [[renal artery stenosis]] (see PRECAUTIONS). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or [[serum creatinine]], usually reversible upon discontinuation of enalaprilat and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients.
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| ====Hematology====
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| * Small decreases in [[hemoglobin]] and [[hematocrit]] (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or [[congestive heart failure]] patients treated with enalaprilat but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. [[Hemolytic anemia]], including cases of hemolysis in patients with [[G-6-PD deficiency]], has been reported; a causal relationship to enalapril cannot be excluded.
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| ====Liver Function Tests====
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| * Elevations of liver enzymes and/or [[serum bilirubin]] have occurred (see WARNINGS, Hepatic Failure).
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| |postmarketing=FDA Package Insert for {{PAGENAME}} contains no information regarding ''Postmarketing Experience''.
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| |useInPed=* The effects of enalapril maleate as an Antihypertensive have been established in hypertensive pediatric patients age 1 month to 16 years. Use of enalapril maleate in these age groups is supported by evidence from adequate and well-controlled studies of enalapril maleate in pediatric and adult patients as well as by published literature in pediatric patients.
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| * For pediatric hypertensive patients, the usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Dosage should be adjusted according to blood pressure response. Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients.
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| * Enalapril maleate is not recommended in neonates and in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m2, as no data are available.
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| |useInGeri=FDA Package Insert for {{PAGENAME}} contains no information regarding ''Geriatrics''.
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| |useInGender=FDA Package Insert for {{PAGENAME}} contains no information regarding ''Gender''.
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| |useInRace=FDA Package Insert for {{PAGENAME}} contains no information regarding ''Race''.
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| |mechAction=* Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of [[angiotensin I]] to the vasoconstrictor substance, [[angiotensin II]]. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril 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. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalaprilat alone for up to 48 weeks, mean increases in serum [[potassium]] of approximately 0.2 mEq/L were observed. In patients treated with enalaprilat plus a [[thiazide diuretic]], there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma [[renin]] activity.
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| * 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 enalaprilat remains to be elucidated.
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| * While the mechanism through which enalaprilat lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalaprilat is antihypertensive even in patients with low-renin hypertension. Although enalaprilat was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non-black patients.
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| |PD=* Administration of enalaprilat to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients (see WARNINGS).
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| * In most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours.
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| * At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval (see DOSAGE AND ADMINISTRATION).
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| * In some patients achievement of optimal blood pressure reduction may require several weeks of therapy.
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| * The antihypertensive effects of enalaprilat have continued during long term therapy. Abrupt withdrawal of enalaprilat has not been associated with a rapid increase in blood pressure.
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| * In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalaprilat, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with [[renovascular hypertension]].
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| * When given together with thiazide-type diuretics, the blood pressure lowering effects of enalaprilat are approximately additive.
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| |PK=* Following oral administration of VASOTEC, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of VASOTEC is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat.
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| * The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.
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| * The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With [[glomerular filtration rate]] ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of [[renal insufficiency]] (see DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min.
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| * Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C-enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
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