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| {{DrugProjectFormSinglePage
| | #REDIRECT [[Enalapril maleate]] |
| |authorTag={{AZ}}, {{AM}}
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| |genericName=Enalaprilat
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| |aOrAn=an
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| |drugClass=Angiontensin converting enzyme inhibitor
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| |indication=[[hypertension]], [[ malignant hypertension]] and adjunct in Kidney imaging when there is underlying [[renovascular hypertension]]
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| |hasBlackBoxWarning=Yes
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| |adverseReactions=[[hyperkalemia]] (1% ), [[nausea]] (1.1% ), [[headache]] (2.9% )
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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, Enalaprilat Injection, USP should be discontinued as soon as possible.
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| |fdaLIADAdult=*Hypertension
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| :* Dosing Information
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| :: Hypertension ( without diuretics): 1.25 mg IV over 5 minutes every 6 hours (MAX 5 mg/dose)
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| :: Hypertension ( with diuretics)
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| ::: Initial: 0.625 mg IV over 5 minutes, may repeated after 1 hour as needed,
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| ::: Maintenance: 1.25 mg IV every 6 hours
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| |fdaLIADPed=FDA Package Insert for {{PAGENAME}} contains no information regarding ''safety and efficacy in pediatric patients''.
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| |offLabelPedGuideSupport=FDA Package Insert for {{PAGENAME}} contains no information regarding ''guidelines in pediatric patients''.
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| |contraindications=* History of [[hypersensitivity]] or [[angioedema]] related to previous treatment with an [[angiotensin converting enzyme inhibitor]].
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| * Patients with hereditary or idiopathic angioedema.
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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=* 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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| |drugInteractions=====Hypotension====
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| '''''Patients on Diuretic Therapy'''''
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| * Patients on [[diuretics]] and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION).
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| ====Agents Causing Renin Release====
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| * The antihypertensive effect of enalaprilat is augmented by antihypertensive agents that cause [[renin]] release (e.g., diuretics).
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| ====Non-steroidal Anti-inflammatory Agents====
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| * In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible.
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| * In a clinical pharmacology study, [[indomethacin]] or [[sulindac]] was administered to hypertensive patients receiving enalaprilat. In this study there was no evidence of a blunting of the antihypertensive action of enalaprilat. However, reports suggest that [[NSAIDs]] may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
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| ====Other Cardiovascular Agents====
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| * Enalaprilat has been used concomitantly with [[beta adrenergic-blocking agents]], [[methyldopa]], [[nitrates]], [[calcium-blocking agents]], [[hydralazine]], [[prazosin]] and [[digoxin]] without evidence of clinically significant adverse interactions.
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| ====Agents Increasing Serum Potassium====
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| * Enalaprilat attenuates potassium loss caused by [[thiazide-type diuretics]]. [[Potassium-sparing diuretics]] (e.g., [[spironolactone]], [[triamterene]], or [[amiloride]]), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. [[Potassium]] sparing agents should generally not be used in patients with heart failure receiving enalaprilat.
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| ====Lithium====
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| * [[Lithium toxicity]] has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalaprilat and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.
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| ====Gold====
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| * Nitritoid reactions (symptoms include [[facial flushing]], [[nausea]], [[vomiting]] and [[hypotension]]) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalaprilat.
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| ====Carcinogenesis, Mutagenesis, Impairment of Fertility====
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| * There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.
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| * Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.
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| * There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).
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| }}
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