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enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril of action antihypertensive the of blunting a of evidence no was there study this In maleate. enalapril

In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving receiving patients hypertensive to administered was sulindac or indomethacin study, pharmacology clinical a In maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This

of renal function. These effects are usually reversible. usually are effects These function. renal of interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.

with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration further a in result may enalapril of co-administration the drugs, anti-inflammatory non-steroidal with Other Cardiovascular Agents: Enalaprilat Injection has been used concomitantly with digitalis, beta

: In some patients with compromised renal function who are being treated treated being are who function renal compromised with patients some In : Non-steroidal Anti-inflammatory Agents Anti-inflammatory Non-steroidal adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without

antihypertensive agents that cause renin release (e.g., diuretics). (e.g., release renin cause that agents antihypertensive evidence of clinically significant adverse interactions.

: The antihypertensive effect of Enalaprilat Injection appears to be augmented by augmented be to appears Injection Enalaprilat of effect antihypertensive The : Agents Causing Renin Release Renin Causing Agents Agents Increasing Serum Potassium: Enalaprilat Injection attenuates potassium loss caused by thiazide-type

WARNINGS .) least one hour after the initial dose of enalaprilat. (See (See enalaprilat. of dose initial the after hour one least diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or

of treatment with enalaprilat. If it is necessary to continue the diuretic, provide close medical supervision for at for supervision medical close provide diuretic, the continue to necessary is it If enalaprilat. with treatment of potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if

of an intravenous infusion of normal saline, discontinuing the diuretic or increasing the salt intake prior to initiation to prior intake salt the increasing or diuretic the discontinuing saline, normal of infusion intravenous an of concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with

therapy with enalaprilat. The possibility of hypotensive effects with enalaprilat can be minimized by administration administration by minimized be can enalaprilat with effects hypotensive of possibility The enalaprilat. with therapy caution and with frequent monitoring of serum potassium.

was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of initiation after pressure blood of reduction excessive an experience occasionally may instituted, recently was Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause

: Patients on diuretics and especially those in whom diuretic therapy diuretic whom in those especially and diuretics on Patients : Hypotension—Patients on Diuretic Therapy Diuretic on Hypotension—Patients elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients

rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. inhibitor ACE concomitant and aurothiomalate) (sodium gold injectable with therapy on patients in rarely receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is

Gold: Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported been have hypotension) and vomiting nausea, flushing, facial include (symptoms reactions Nitritoid recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with

Drug Interactions Interactions Drug lithium.

occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. expansion. volume by corrected be can it mechanism, this to due be to considered is and occurs Carcinogenesis, Mutagenesis, Impairment of Fertility

hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension If release. renin compensatory to secondary formation II angiotensin block may enalapril hypotension, Carcinogenicity studies have not been done with Enalaprilat Injection.

: In patients undergoing major surgery or during anesthesia with agents that produce that agents with anesthesia during or surgery major undergoing patients In : Surgery/Anesthesia Enalaprilat Injection is the bioactive form of its ethyl ester, enalapril maleate. There was no evidence of a

inhibitor-induced cough should be considered in the differential diagnosis of cough. of diagnosis differential the in considered be should cough inhibitor-induced tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to

cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE ACE therapy. of discontinuation after resolving always inhibitors, ACE all with reported been has cough 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

: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive persistent bradykinin, endogenous of degradation the of inhibition the to due Presumably : Cough doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily

Drug Interactions Drug .) with Enalaprilat Injection. (See (See Injection. Enalaprilat with dose (MRHDD) when compared on a body surface area basis.

concomitant use of potassium-sparing agents or potassium supplements, which should be used cautiously, if at all, at if cautiously, used be should which supplements, potassium or agents potassium-sparing of use concomitant Enalaprilat Injection was not mutagenic in the Ames microbial mutagen test with or without metabolic activation.

patients. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the and mellitus, diabetes insufficiency, renal include hyperkalemia of development the for factors Risk patients. Enalapril showed no drug-related changes in the following genotoxicity studies: rec-assay, reverse mutation assay

despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive hypertensive of percent 0.28 in therapy of discontinuation of cause a was Hyperkalemia therapy. continued despite with E. coli, sister chromatid exchange with cultured mammalian cells, the micronucleus test with mice, and in an

hypertensive patients in clinical trials receiving enalapril. In most cases these were isolated values which resolved which values isolated were these cases most In enalapril. receiving trials clinical in patients hypertensive in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance of

: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of percent one approximately in observed was mEq/L) 5.7 than (greater potassium serum Elevated : Hyperkalemia male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body

ADMINISTRATION .) surface area basis).

DOSAGE AND AND DOSAGE function. renal of assessment include always should patient hypertensive the of Evaluation (See (See Pregnancy

reduction of enalaprilat and/or discontinuation of the diuretic may be required. required. be may diuretic the of discontinuation and/or enalaprilat of reduction Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal

concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage Dosage impairment. renal pre-existing with patients in occur to likely more is This diuretic. a with concomitantly Morbidity and Mortality.

blood urea and serum creatinine, usually minor and transient, especially when enalaprilat has been given been has enalaprilat when especially transient, and minor usually creatinine, serum and urea blood Nursing Mothers

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in increases developed have disease vascular renal pre-existing apparent no with patients hypertensive Some Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse

. . patients renal function should be monitored during the first few weeks of therapy of weeks few first the during monitored be should function renal patients reactions in nursing infants from enalapril, a decision should be made whether to discontinue nursing or to

were almost always reversible upon discontinuation of enalapril or enalaprilat and/or diuretic therapy. In such In therapy. diuretic and/or enalaprilat or enalapril of discontinuation upon reversible always almost were discontinue Enalaprilat Injection, taking into account the importance of the drug to the mother.

urea nitrogen and serum creatinine were observed in 20 percent of patients receiving enalapril. These increases These enalapril. receiving patients of percent 20 in observed were creatinine serum and nitrogen urea Pediatric Use

In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood blood in increases stenosis, artery renal bilateral or unilateral with patients hypertensive in studies clinical In Safety and effectiveness in pediatric patients have not been established.

azotemia and rarely with acute renal failure and/or death. and/or failure renal acute with rarely and azotemia Geriatric Use

converting enzyme inhibitors, including enalapril or enalaprilat, may be associated with oliguria and/or progressive and/or oliguria with associated be may enalaprilat, or enalapril including inhibitors, enzyme converting Clinical studies of Enalaprilat Injection did not include sufficient numbers of subjects aged 65 and over to determine

function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin angiotensin with treatment system, renin-angiotensin-aldosterone the of activity the on depend may function whether they respond differently from younger subjects. Other reported clinical experience has not identified

renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal whose failure heart severe with patients In individuals. susceptible in anticipated be may function renal differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in changes system, renin-angiotensin-aldosterone the inhibiting of consequence a As Impaired Renal Function: Function: Renal Impaired should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of

patients with obstruction in the outflow tract of the left ventricle. left the of tract outflow the in obstruction with patients decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

: As with all vasodilators, enalapril should be given with caution to caution with given be should enalapril vasodilators, all with As : Aortic Stenosis/Hypertrophic Cardiomyopathy Stenosis/Hypertrophic Aortic This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be

General General greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal PRECAUTIONS PRECAUTIONS function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include

assessment of renal function. (See DOSAGE AND ADMINISTRATION.) (MRHDD). (MRHDD).

basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose daily human recommended maximum the respectively, times, 12 and times 57 were used doses the basis, ADVERSE REACTIONS

No teratogenic effects of oral enalapril were seen in studies of pregnant rats and rabbits. On a body surface area area surface body a On rabbits. and rats pregnant of studies in seen were enalapril oral of effects teratogenic No Enalaprilat Injection has been found to be generally well tolerated in controlled clinical trials involving 349 patients

although there is no experience with the latter procedure. latter the with experience no is there although (168 with hypertension, 153 with congestive heart failure and 28 with coronary artery disease). The most frequent

by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, exchange by removed be may theoretically and benefit, clinical some with dialysis peritoneal by clinically significant adverse experience was hypotension (3.4 percent), occurring in eight patients (5.2 percent)

for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation circulation neonatal from removed been has placenta, the crosses which Enalapril, function. renal disordered for with congestive heart failure, three (1.8 percent) with hypertension and one with coronary artery disease. Other

perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting and/or hypotension reversing of means as required be may dialysis or transfusion Exchange perfusion. adverse experiences occurring in greater than one percent of patients were: headache (2.9 percent) and nausea

and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal and pressure blood of support toward directed be should attention occurs, oliguria If hyperkalemia. and (1.1 percent).

Infants with histories of of histories with Infants exposure to ACE inhibitors should be closely observed for hypotension, oliguria, oliguria, hypotension, for observed closely be should inhibitors ACE to exposure in utero utero in Adverse experiences occurring in 0.5 to 1.0 percent of patients in controlled clinical trials included: myocardial

oligohydramnios may not appear until after the fetus has sustained irreversible injury. irreversible sustained has fetus the after until appear not may oligohydramnios infarction, fatigue, dizziness, fever, rash and constipation.

. Patients and physicians should be aware, however, that that however, aware, be should physicians and Patients . appropriate, depending upon the week of pregnancy of week the upon depending appropriate, Angioedema: Angioedema has been reported in patients receiving enalaprilat, with an incidence higher in black

the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be be may (BPP) profiling biophysical or (NST), test non-stress a (CST), testing stress Contraction mother. the than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face,

If oligohydramnios is observed, Enalaprilat Injection should be discontinued unless it is considered lifesaving for lifesaving considered is it unless discontinued be should Injection Enalaprilat observed, is oligohydramnios If extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and

ultrasound examinations should be performed to assess the intraamniotic environment. intraamniotic the assess to performed be should examinations ultrasound appropriate therapy instituted immediately (see WARNINGS).

found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial serial and fetuses, their to hazards potential the of apprised be should mothers the cases, rare these In found. Cough: See PRECAUTIONS, Cough.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be will inhibitors ACE to alternative no pregnancies), thousand every in once than often less (probably Rarely Enalapril Maleate

effort to discontinue the use of Enalaprilat Injection as soon as possible. as soon as Injection Enalaprilat of use the discontinue to effort Since enalapril is converted to enalaprilat, those adverse experiences associated with enalapril might also be

trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every every make should physicians pregnant, become patients when Nonetheless, informed. so be should trimester expected to occur with Enalaprilat Injection.

limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first the during only inhibitors ACE to exposed are fetuses and embryos whose Mothers trimester. first the to limited The following adverse experiences have been reported with enalapril and, within each category, are listed in

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been has that exposure ACE-inhibitor intrauterine from resulted have to appear not do effects adverse These order of decreasing severity.

been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure. exposure. ACE-inhibitor the to due were occurrences these whether clear not is it although reported, been Body As A Whole: Syncope, orthostatic effects, anaphylactoid reactions (see WARNINGS, Anaphylactoid

hypoplastic lung development. Prematurity development. lung hypoplastic , intrauterine growth retardation, and patent ductus arteriosus have also have arteriosus ductus patent and retardation, growth intrauterine , Reactions During Membrane Exposure), chest pain, abdominal pain, asthenia.

oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and deformation, craniofacial contractures, limb fetal with associated been has setting this in oligohydramnios Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to

death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; function; renal fetal decreased from resulting presumably reported, been also has Oligohydramnios death. excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction;

, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and failure, renal irreversible or reversible anuria, hypoplasia, skull neonatal hypotension, including , neonatal injury neonatal pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; orthostatic

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and fetal with associated been has pregnancy of trimesters third and second the during inhibitors ACE of use The hypotension; angina pectoris; palpitation, Raynaud's phenomenon.

discontinued as soon as possible. possible. as soon as discontinued Digestive: IIeus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic

dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be should inhibitors ACE detected, is pregnancy When literature. world the in reported been have cases dozen jaundice) (see WARNINGS, Hepatic Failure), melena, diarrhea, vomiting, dyspepsia, anorexia, glossitis, stomatitis,

ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several women. pregnant to administered when death and morbidity neonatal and fetal cause can inhibitors ACE dry mouth.

Fetal/Neonatal Morbidity and Mortality Mortality and Morbidity Fetal/Neonatal Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression.

ACE inhibitor and receive appropriate medical follow-up. medical appropriate receive and inhibitor ACE Musculoskeletal: Muscle cramps.

receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the discontinue should enzymes hepatic of elevations marked or jaundice develop who inhibitors ACE receiving Nervous/Psychiatric: Depression, vertigo, confusion, ataxia, somnolence, insomnia, nervousness, peripheral

to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients understood. not is syndrome this of mechanism The death. (sometimes) and necrosis, hepatic fulminant to neuropathy (e.g., paresthesia, dysesthesia), dream abnormality.

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses progresses and jaundice cholestatic with starts that syndrome a with associated been have inhibitors ACE Rarely, Respiratory: Bronchospasm, dyspnea, pneumonia, bronchitis, cough, rhinorrhea, sore throat and hoarseness,

Hepatic Failure Hepatic asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis.

be considered. considered. be Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster,

Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should should disease renal and disease vascular collagen with patients in counts cell blood white of monitoring Periodic erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.

revealed cases of neutropenia, or agranulocytosis in which a causal relationship to enalapril cannot be excluded. be cannot enalapril to relationship causal a which in agranulocytosis or neutropenia, of cases revealed Special Senses: Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing.

insufficient to show that enalapril does not cause agranulocytosis in similar rates. Marketing experience has experience Marketing rates. similar in agranulocytosis cause not does enalapril that show to insufficient Urogenital: Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION),

especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are are enalapril of trials clinical from data Available disease. vascular collagen a have also they if especially urinary tract infection, flank pain, gynecomastia, impotence.

marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment renal with patients in frequently more but patients uncomplicated in rarely depression, marrow Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive

Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone and agranulocytosis cause to shown been has captopril, inhibitor, enzyme converting angiotensin Another ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis,

Neutropenia/Agranulocytosis Neutropenia/Agranulocytosis leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations.

also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. absorption. sulfate dextran with apheresis lipoprotein low-density undergoing patients in reported been also Hypotension: Combining the results of clinical trials in patients with hypertension or congestive heart failure,

dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have reactions Anaphylactoid inhibitor. ACE an with concomitantly treated and membranes high-flux with dialyzed hypotension (including postural hypotension, and other orthostatic effects) was reported in 2.3 percent of patients

Anaphylactoid Reactions During Membrane Exposure: Exposure: Membrane During Reactions Anaphylactoid Anaphylactoid reactions have been reported in patients patients in reported been have reactions Anaphylactoid following the initial dose of enalapril or during extended therapy. In the hypertensive patients, hypotension

inadvertent rechallenge. rechallenge. inadvertent occurred in 0.9 percent and syncope occurred in 0.5 percent of patients. Hypotension or syncope was a cause for

patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon reappeared they but withheld, temporarily were inhibitors ACE when avoided were reactions these patients, discontinuation of therapy in 0.1 percent of hypertensive patients. (See WARNINGS.)

hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same same the In reactions. anaphylactoid life-threatening sustained inhibitors ACE receiving while venom hymenoptera Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Anaphylactoid Reactions During Desensitization: Desensitization: During Reactions Anaphylactoid Two patients undergoing desensitizing treatment with treatment desensitizing undergoing patients Two Clinical Laboratory Test Findings

CONTRAINDICATIONS USAGE AND INDICATIONS ). ). and angioedema while receiving an ACE inhibitor (see also also (see inhibitor ACE an receiving while angioedema Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of of risk increased at be may therapy inhibitor ACE to unrelated angioedema of history a with Patients Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum

measures necessary to ensure a patent airway, should be promptly provided. provided. promptly be should airway, patent a ensure to necessary measures ADVERSE REACTIONS ADVERSE (See (See .) creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with

, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or and/or mL) 0.5 to mL (0.3 1:1000 solution epinephrine subcutaneous e.g., , obstruction, appropriate therapy appropriate obstruction, essential hypertension treated with enalapril alone. Increases are more likely to occur in patients receiving

Where there is involvement of the tongue, glottis or larynx, likely to cause airway airway cause to likely larynx, or glottis tongue, the of involvement is there Where edema may be fatal. fatal. be may edema concomitant diuretics or in patients with renal artery stenosis. (See PRECAUTIONS.)

treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal with associated Angioedema symptoms. relieving in useful been have antihistamines although treatment, Hematology: Small decreases in hemoglobin and hematocrit (mean decreases of approximately

instances where swelling has been confined to the face and lips the condition has generally resolved without resolved generally has condition the lips and face the to confined been has swelling where instances 0.3 g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with enalapril but

monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In In occurred. has symptoms and signs of resolution sustained and complete until provided be should monitoring are rarely of clinical importance unless another cause of anemia co-exists. In clinical trials, less than 0.1 percent

treatment. In such cases, Enalaprilat Injection should be promptly discontinued and appropriate therapy and therapy appropriate and discontinued promptly be should Injection Enalaprilat cases, such In treatment. of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with

treated with angiotensin converting enzyme inhibitors, including enalaprilat. This may occur at any time during time any at occur may This enalaprilat. including inhibitors, enzyme converting angiotensin with treated G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded.

Angioedema: Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients patients in reported been has larynx and/or glottis tongue, lips, extremities, face, the of Angioedema Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic

may be subject to a variety of adverse reactions, some of them serious. serious. them of some reactions, adverse of variety a to subject be may Failure).

polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Enalaprilat Injection) Enalaprilat (including inhibitors ACE receiving patients bradykinin, endogenous including polypeptides, OVERDOSAGE

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and and eicosanoids of metabolism the affect inhibitors enzyme angiotensin-converting because Presumably In clinical studies, some hypertensive patients received a maximum dose of 80 mg of enalaprilat intravenously over

Anaphylactoid and Possibly Related Reactions Related Possibly and Anaphylactoid a fifteen minute period. At this high dose, no adverse effects beyond those as associated with the recommended

which usually can be given without difficulty once the blood pressure has increased after volume expansion. expansion. volume after increased has pressure blood the once difficulty without given be can usually which dosages were observed.

intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, doses, further to contraindication a not is response hypotensive transient A saline. normal of infusion intravenous A single intravenous dose of ≤4167 mg/kg of enalaprilat was associated with lethality in female mice.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an an receive necessary, if and, position supine the in placed be should patient the occurs, hypotension If No lethality occurred after an intravenous dose of 3472 mg/kg.

result in a myocardial infarction or cerebrovascular accident. cerebrovascular or infarction myocardial a in result The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be

to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could could pressure blood in fall excessive an whom in disease, cerebrovascular or heart ischemic with patients to intravenous infusion of normal saline solution.

closely whenever the dose of enalaprilat is adjusted and/or diuretic is increased. Similar considerations may apply may considerations Similar increased. is diuretic and/or adjusted is enalaprilat of dose the whenever closely Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal

the potential for an excessive fall in blood pressure especially in these patients, therapy should be followed be should therapy patients, these in especially pressure blood in fall excessive an for potential the circulation by peritoneal dialysis. (See WARNINGS, Anaphylactoid Reactions During Membrane Exposure.)

associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of of Because death. and/or failure renal acute with rarely and azotemia, progressive and/or oliguria with associated DOSAGE AND ADMINISTRATION

heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be may and observed been has hypotension excessive insufficiency, renal associated without or with failure, heart FOR INTRAVENOUS ADMINISTRATION ONLY

PRECAUTIONS, PRECAUTIONS, DOSAGE AND ADMINISTRATION AND DOSAGE REACTIONS, ADVERSE Interactions, Drug .) In patients with patients In .)

and and The dose in hypertension is 1.25 mg every six hours administered intravenously over a five minute period. A clinical

Injection in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See (See adjustments. such tolerate to able are who hypotension excessive for risk at patients in Injection response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to four hours after

the diuretic, reduce the diuretic dose or increase salt intake cautiously before initiating therapy with Enalaprilat with therapy initiating before cautiously intake salt increase or dose diuretic the reduce diuretic, the dosing. The peak effects of the second and subsequent doses may exceed those of the first.

. It may be advisable to eliminate to advisable be may It .

diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology any of depletion salt and/or volume severe or dialysis, renal dose, diuretic No dosage regimen for enalaprilat injection has been clearly demonstrated to be more effective in treating

or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in in increase or diuresis intensive recent therapy, diuretic dose high hyponatremia, failure, heart characteristics: or hypertension than 1.25 mg every six hours. However, in controlled clinical studies in hypertension, doses as high

progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions following the with those include death, and/or failure renal acute with rarely and azotemia, progressive as 5 mg every six hours were well tolerated for up to 36 hours. There has been inadequate experience with doses

patients on dialysis. Patients at risk for excessive hypotension, sometimes associated with oliguria and/or oliguria with associated sometimes hypotension, excessive for risk at Patients dialysis. on patients greater than 20 mg per day.

enalaprilat especially in severely salt/volume depleted persons such as those treated vigorously with diuretics or or diuretics with vigorously treated those as such persons depleted salt/volume severely in especially enalaprilat In studies of patients with hypertension, enalaprilat injection has not been administered for periods longer than

Excessive hypotension is rare in uncomplicated hypertensive patients but is a possible consequence of the use of use the of consequence possible a is but patients hypertensive uncomplicated in rare is hypotension Excessive 48 hours. In other studies, patients have received enalaprilat injection for as long as seven days.

Hypotension The dose for patients being converted to enalaprilat injection from oral therapy for hypertension with enalapril

WARNINGS WARNINGS maleate is 1.25 mg every six hours. For conversion from intravenous to oral therapy, the recommended initial dose

and in patients with hereditary or idiopathic angioedema. angioedema. idiopathic or hereditary with patients in and of Enalapril Maleate Tablets is 5 mg once a day with subsequent dosage adjustments as necessary.

patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor enzyme converting angiotensin an with treatment previous to related angioedema of history a with patients Patients on Diuretic Therapy

Enalaprilat Injection is contraindicated in patients who are hypersensitive to any component of this product and in in and product this of component any to hypersensitive are who patients in contraindicated is Injection Enalaprilat For patients on diuretic therapy the recommended starting dose for hypertension is 0.625 mg administered

CONTRAINDICATIONS CONTRAINDICATIONS intravenously over a five minute period; also see below, Patients at Risk of Excessive Hypotension. A clinical

Angioedema WARNINGS, .) .) non-blacks. (See (See non-blacks. response is usually seen within 15 minutes. Peak effects after the first dose may not occur for up to four hours after

patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to to compared angioedema of incidence higher a have to reported been have inhibitors ACE receiving patients dosing, although most of the effect is usually apparent within the first hour. If after one hour there is an inadequate

an effect on blood pressure that is less in black patients than in non-blacks. In addition, it should be noted that black that noted be should it addition, In non-blacks. in than patients black in less is that pressure blood on effect an clinical response, the 0.625 mg dose may be repeated. Additional doses of 1.25 mg may be administered at six hour

In considering use of Enalaprilat Injection, it should be noted that in controlled clinical trials ACE inhibitors have inhibitors ACE trials clinical controlled in that noted be should it Injection, Enalaprilat of use considering In intervals.

WARNINGS risk. (See (See risk. .) .) For conversion from intravenous to oral therapy, the recommended initial dose of Enalapril Maleate Tablets for

vascular disease, and that available data are insufficient to show that Enalaprilat Injection does not have a similar a have not does Injection Enalaprilat that show to insufficient are data available that and disease, vascular patients who have responded to 0.625 mg of enalaprilat every six hours is 2.5 mg once a day with subsequent

enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen or impairment renal with patients in particularly agranulocytosis, caused has captopril, inhibitor, enzyme dosage adjustment as necessary.

In using Enalaprilat Injection, consideration should be given to the fact that another angiotensin converting converting angiotensin another that fact the to given be should consideration Injection, Enalaprilat using In Dosage Adjustment in Renal Impairment with a variety of other antihypertensive agents, without apparent difficulty except for occasional hypotension. occasional for except difficulty apparent without agents, antihypertensive other of variety a with The usual dose of 1.25 mg of enalaprilat every six hours is recommended for patients with a creatinine clearance

≤ approximately additive effects on blood pressure. Enalapril, the pro-drug of enalaprilat, has been used extensively used been has enalaprilat, of pro-drug the Enalapril, pressure. blood on effects additive approximately >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance 30 mL/min

≥ Enalaprilat Injection has been studied with only one other antihypertensive agent, furosemide, which showed showed which furosemide, agent, antihypertensive other one only with studied been has Injection Enalaprilat (serum creatinine 3 mg/dL), the initial dose is 0.625 mg. (See WARNINGS.)

Enalaprilat Injection is indicated for the treatment of hypertension when oral therapy is not practical. not is therapy oral when hypertension of treatment the for indicated is Injection Enalaprilat If after one hour there is an inadequate clinical response, the 0.625 mg dose may be repeated. Additional doses INDICATIONS AND USAGE USAGE AND INDICATIONS of 1.25 mg may be administered at six hour intervals.

For dialysis patients, see below, Patients at Risk of Excessive Hypotension.

Drug Interactions Drug PRECAUTIONS, ). ).

maleate (see (see maleate For conversion from intravenous to oral therapy, the recommended initial dose of Enalapril Maleate Tablets is

enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril of action antihypertensive the of blunting a of evidence no was there study this In maleate. enalapril 5 mg once a day for patients with creatinine clearance >30 mL/min and 2.5 mg once daily for patients with

In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving patients hypertensive to administered was sulindac or indomethacin study, pharmacology clinical a In creatinine clearance ≤30 mL/min. Dosage should then be adjusted according to blood pressure response.

usually unchanged. The effects appear to be similar in patients with renovascular hypertension. hypertension. renovascular with patients in similar be to appear effects The unchanged. usually Patients at Risk of Excessive Hypotension

Following administration of enalapril, there is an increase in renal blood flow; glomerular filtration rate is rate filtration glomerular flow; blood renal in increase an is there enalapril, of administration Following Hypertensive patients at risk of excessive hypotension include those with the following concurrent conditions or

duration of action in most patients is approximately six hours. six approximately is patients most in action of duration characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in

The duration of hemodynamic effects appears to be dose-related. However, for the recommended dose, the the dose, recommended the for However, dose-related. be to appears effects hemodynamic of duration The diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology (see WARNINGS). Single doses

enalaprilat has not been associated with a rapid increase in blood pressure. blood in increase rapid a with associated been not has enalaprilat of enalaprilat as low as 0.2 mg have produced excessive hypotension in normotensive patients with these

minutes of administration with the maximum effect occurring within one to four hours. The abrupt withdrawal of withdrawal abrupt The hours. four to one within occurring effect maximum the with administration of minutes diagnoses. Because of the potential for an extreme hypotensive response in these patients, therapy should be

WARNINGS ). The onset of action usually occurs within fifteen fifteen within occurs usually action of onset The ).

be anticipated in volume-depleted patients (see (see patients volume-depleted in anticipated be started under very close medical supervision. The starting dose should be no greater than 0.625 mg administered

usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might it although infrequent, therefore is hypotension postural Symptomatic component. orthostatic no with usually intravenously over a period of no less than five minutes and preferably longer (up to one hour).

Enalaprilat Injection results in the reduction of both supine and standing systolic and diastolic blood pressure, blood diastolic and systolic standing and supine both of reduction the in results Injection Enalaprilat Patients should be followed closely whenever the dose of enalaprilat is adjusted and/or diuretic is increased.

Pharmacodynamics Pharmacodynamics Administration

cross the placenta following administration of labeled drug to pregnant hamsters. hamsters. pregnant to drug labeled of administration following placenta the cross Enalaprilat Injection should be administered as a slow intravenous infusion, as indicated above. It may be

C enalapril maleate. Radioactivity was found to found was Radioactivity maleate. enalapril C of administration following radioactivity contains rats lactating in

14 administered as provided or diluted with up to 50 mL of a compatible diluent. Parenteral drug products should be

barrier poorly, if at all. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk Milk tissues. any in accumulation in result not do rats in maleate enalapril of doses Multiple all. at if poorly, barrier inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.

Studies in dogs indicate that enalaprilat does not enter the brain, and that enalapril crosses the blood-brain the crosses enalapril that and brain, the enter not does enalaprilat that indicate dogs in Studies Compatibility and Stability

ADMINISTRATION

.) Enalaprilat is dialyzable at the rate of 62 mL/min. 62 of rate the at dialyzable is Enalaprilat .) Enalaprilat Injection as supplied and mixed with the following intravenous diluents has been found to maintain full

DOSAGE AND AND DOSAGE

The effective half-life of enalaprilat is prolonged at this level of renal insufficiency. (See (See insufficiency. renal of level this at prolonged is enalaprilat of half-life effective The activity for 24 hours at room temperature:

trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. be may state steady to time and increases concentration peak to time increase, levels enalaprilat trough 5 percent Dextrose Injection

30 mL/min, peak and peak mL/min, 30 rate filtration glomerular With less. or mL/min 30 is rate filtration glomerular the until function

≤ 0.9 percent Sodium Chloride Injection

The disposition of enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal renal normal with patients in that to similar is insufficiency renal with patients in enalaprilat of disposition The 0.9 percent Sodium Chloride Injection in 5 percent Dextrose

following oral administration. oral following 5 percent Dextrose in Lactated Ringer's Injection

an administered dose recovered in the urine as unchanged drug within 24 hours. Enalaprilat is poorly absorbed poorly is Enalaprilat hours. 24 within drug unchanged as urine the in recovered dose administered an B. Braun ISOLYTE***E. enalapril maleate, is approximately 11 hours. Excretion of enalaprilat is primarily renal with more than 90 percent of of percent 90 than more with renal primarily is enalaprilat of Excretion hours. 11 approximately is maleate, enalapril

The effective half-life for accumulation of enalaprilat, as determined from oral administration of multiple doses of doses multiple of administration oral from determined as enalaprilat, of accumulation for half-life effective The HOW SUPPLIED

that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. of site saturable a indicating dose, with increase not does bound amount The ACE. to bound been has that Enalaprilat Injection, USP 1.25 mg per mL, is a clear, colorless solution and is supplied as follows:

polyexponential with a prolonged terminal phase, apparently representing a small fraction of the administered dose dose administered the of fraction small a representing apparently phase, terminal prolonged a with polyexponential NDC Container Concentration Fill Quantity

Following intravenous administration of a single dose, the serum concentration profile of enalaprilat is enalaprilat of profile concentration serum the dose, single a of administration intravenous Following 0409-2122-01 Vial 1.25 mg/mL 1 mL 1 per Box

Pharmacokinetics and Metabolism Metabolism and Pharmacokinetics 0409-2122-02 Vial 1.25 mg/mL 2 mL 1 per Box

smaller average response to enalaprilat monotherapy than non-black patients. patients. non-black than monotherapy enalaprilat to response average smaller

hypertension. In clinical studies, black hypertensive patients (usually a low-renin hypertensive population) had a had population) hypertensive low-renin a (usually patients hypertensive black studies, clinical In hypertension. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

the renin-angiotensin-aldosterone system, enalaprilat has antihypertensive activity even in patients with low-renin with patients in even activity antihypertensive has enalaprilat system, renin-angiotensin-aldosterone the ***Registered trademark of B. Braun

While the mechanism through which enalaprilat lowers blood pressure is believed to be primarily suppression of of suppression primarily be to believed is pressure blood lowers enalaprilat which through mechanism the While

potent vasodepressor peptide, play a role in the therapeutic effects of enalaprilat remains to be elucidated. be to remains enalaprilat of effects therapeutic the in role a play peptide, vasodepressor potent Revised: March, 2010

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a bradykinin, of levels increased Whether bradykinin. degrades that enzyme an kininase, to identical is ACE

increased plasma renin activity. activity. renin plasma increased

PRECAUTIONS .) Removal of angiotensin II negative feedback on renin secretion leads to leads secretion renin on feedback negative II angiotensin of Removal .) (See potassium. serum in

mEq/L were observed. In patients treated with enalapril plus a thiazide diuretic, there was essentially no change no essentially was there diuretic, thiazide a plus enalapril with treated patients In observed. were mEq/L 0.2

patients treated with enalapril alone for up to 48 weeks, mean increases in serum potassium of approximately approximately of potassium serum in increases mean weeks, 48 to up for alone enalapril with treated patients

secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive In potassium. serum of increases small in results it small, is decrease latter the Although secretion.

in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone decreased to and activity vasopressor decreased to leads which II, angiotensin plasma decreased in

angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results results ACE of Inhibition cortex. adrenal the by secretion aldosterone stimulates also II Angiotensin II. angiotensin

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, vasoconstrictor the to I angiotensin of conversion the catalyzes that dipeptidase peptidyl a is ACE

Intravenous enalaprilat, or oral enalapril, after hydrolysis to enalaprilat, inhibits ACE in human subjects and animals. and subjects human in ACE inhibits enalaprilat, to hydrolysis after enalapril, oral or enalaprilat, Intravenous

Mechanism of Action Action of Mechanism

metabolite of the orally administered pro-drug, enalapril maleate. Enalaprilat is poorly absorbed orally. orally. absorbed poorly is Enalaprilat maleate. enalapril pro-drug, administered orally the of metabolite

Enalaprilat, an angiotensin-converting enzyme (ACE) inhibitor when administered intravenously, is the active the is intravenously, administered when inhibitor (ACE) enzyme angiotensin-converting an Enalaprilat,

CLINICAL PHARMACOLOGY PHARMACOLOGY CLINICAL

alcohol, 9 mg, added as a preservative. May contain sodium hydroxide for pH adjustment. adjustment. pH for hydroxide sodium contain May preservative. a as added mg, 9 alcohol,

Each milliliter contains 1.25 mg enalaprilat (anhydrous equivalent); sodium chloride to adjust tonicity; benzyl tonicity; adjust to chloride sodium equivalent); (anhydrous enalaprilat mg 1.25 contains milliliter Each

methanol and slightly soluble in water. water. in soluble slightly and methanol Enalaprilat is a white to off-white, crystalline powder with a molecular weight of 384.43. It is sparingly soluble in soluble sparingly is It 384.43. of weight molecular a with powder crystalline off-white, to white a is Enalaprilat

Printed in USA

2 5 2 24 18

O and its structural formula is: is: formula structural its and O 2H • O N H

dihydrate. Its molecular formula is C is formula molecular Its dihydrate. Hospira, Inc., Lake Forest, IL 60045 USA converting enzyme inhibitor. It is chemically described as ( as described chemically is It inhibitor. enzyme converting -(1-carboxy-3-phenylpropyl)-L-alanyl]-L-proline N )-1-[ S

Enalaprilat Injection, USP is a sterile aqueous solution for intravenous administration. Enalaprilat is an angiotensin an is Enalaprilat administration. intravenous for solution aqueous sterile a is USP Injection, Enalaprilat

DESCRIPTION DESCRIPTION

Fetal/Neonatal Morbidity and Mortality and Morbidity Fetal/Neonatal WARNINGS, . . See possible. as soon as discontinued

death to the developing fetus. fetus. developing the to death When pregnancy is detected, Enalaprilat Injection, USP should be should USP Injection, Enalaprilat detected, is pregnancy When

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even even and injury cause can inhibitors ACE trimesters, third and second the during pregnancy in used When

USE IN PREGNANCY PREGNANCY IN USE

R R x only only x only x

Enalaprilat Injection, USP USP Injection, Enalaprilat Enalaprilat Injection, USP Injection, Enalaprilat

EN-2436

EN-2436